Phenotypic Mutation 'Arruda' (pdf version)
Allele | Arruda |
Mutation Type |
missense
|
Chromosome | 13 |
Coordinate | 11,658,781 bp (GRCm39) |
Base Change | C ⇒ T (forward strand) |
Gene |
Ryr2
|
Gene Name | ryanodine receptor 2, cardiac |
Synonym(s) | 9330127I20Rik |
Chromosomal Location |
11,567,988-12,121,831 bp (-) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008] PHENOTYPE: Homozygous null mice show embryonic lethality during organogenesis and altered cardiomyocyte morphology. Homozygotes for a phosphorylation defective allele show decreased susceptibility to myocardial infarction-induced heart failure. Homozygotes for the R420W allele show lymphoid organ hypertrophy. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_023868; MGI:99685
|
Mapped | Yes |
Amino Acid Change |
Arginine changed to Glutamine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000021750]
[ENSMUSP00000127991]
[ENSMUSP00000152510]
|
AlphaFold |
no structure available at present |
PDB Structure |
X-ray crystallography-solution NMR hybrid structure of mouse RyR2 domain A [SOLUTION NMR]
Crystal structure of mouse Ryanodine Receptor 2 (residues 1-217) [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 mutant V186M [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 N-terminal domain (1-217) disease mutant A77V [X-RAY DIFFRACTION]
Structure of the first domain of a cardiac Ryanodine Receptor mutant with exon 3 deleted [X-RAY DIFFRACTION]
Crystal structure of mouse ryanodine receptor 2 (2699-2904) [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 (1-217) disease mutant P164S [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 (1-217) disease mutant R169Q [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor 2 (1-217) disease mutant R176Q [X-RAY DIFFRACTION]
Crystal structure of mouse Ryanodine Receptor isoform 2 (RyR2) 1-547 [X-RAY DIFFRACTION]
>> 3 additional structures at PDB <<
|
SMART Domains |
Protein: ENSMUSP00000021750 Gene: ENSMUSG00000021313 AA Change: R3614Q
Domain | Start | End | E-Value | Type |
MIR
|
110 |
165 |
4.19e-2 |
SMART |
MIR
|
172 |
217 |
9.25e-4 |
SMART |
MIR
|
225 |
280 |
1.8e-1 |
SMART |
MIR
|
286 |
376 |
2.22e-24 |
SMART |
Pfam:RYDR_ITPR
|
454 |
648 |
3.1e-65 |
PFAM |
SPRY
|
670 |
808 |
1.56e-30 |
SMART |
Pfam:RyR
|
862 |
952 |
1.8e-36 |
PFAM |
Pfam:RyR
|
976 |
1066 |
1.1e-32 |
PFAM |
SPRY
|
1098 |
1221 |
5.07e-39 |
SMART |
SPRY
|
1423 |
1562 |
7.47e-28 |
SMART |
low complexity region
|
1643 |
1653 |
N/A |
INTRINSIC |
low complexity region
|
1872 |
1891 |
N/A |
INTRINSIC |
Pfam:RYDR_ITPR
|
2122 |
2331 |
1.2e-71 |
PFAM |
low complexity region
|
2372 |
2379 |
N/A |
INTRINSIC |
low complexity region
|
2416 |
2426 |
N/A |
INTRINSIC |
low complexity region
|
2497 |
2510 |
N/A |
INTRINSIC |
Pfam:RyR
|
2700 |
2790 |
1.1e-33 |
PFAM |
Pfam:RyR
|
2820 |
2904 |
7.1e-27 |
PFAM |
PDB:2BCX|B
|
3580 |
3609 |
9e-12 |
PDB |
low complexity region
|
3700 |
3720 |
N/A |
INTRINSIC |
Pfam:RIH_assoc
|
3829 |
3947 |
3.1e-36 |
PFAM |
EFh
|
4026 |
4054 |
1.36e0 |
SMART |
EFh
|
4061 |
4089 |
5.92e1 |
SMART |
low complexity region
|
4218 |
4227 |
N/A |
INTRINSIC |
low complexity region
|
4256 |
4273 |
N/A |
INTRINSIC |
transmembrane domain
|
4278 |
4300 |
N/A |
INTRINSIC |
low complexity region
|
4309 |
4317 |
N/A |
INTRINSIC |
Pfam:RR_TM4-6
|
4332 |
4598 |
5.7e-96 |
PFAM |
Pfam:Ion_trans
|
4710 |
4877 |
8e-16 |
PFAM |
|
Predicted Effect |
possibly damaging
PolyPhen 2
Score 0.491 (Sensitivity: 0.88; Specificity: 0.90)
(Using ENSMUST00000021750)
|
SMART Domains |
Protein: ENSMUSP00000127991 Gene: ENSMUSG00000021313 AA Change: R3614Q
Domain | Start | End | E-Value | Type |
MIR
|
110 |
165 |
4.19e-2 |
SMART |
MIR
|
172 |
217 |
9.25e-4 |
SMART |
MIR
|
225 |
280 |
1.8e-1 |
SMART |
MIR
|
286 |
376 |
2.22e-24 |
SMART |
Pfam:RYDR_ITPR
|
451 |
655 |
3.5e-73 |
PFAM |
SPRY
|
670 |
808 |
1.56e-30 |
SMART |
Pfam:RyR
|
861 |
955 |
1.4e-33 |
PFAM |
Pfam:RyR
|
975 |
1069 |
9.2e-34 |
PFAM |
SPRY
|
1098 |
1221 |
5.07e-39 |
SMART |
SPRY
|
1423 |
1562 |
7.47e-28 |
SMART |
low complexity region
|
1643 |
1653 |
N/A |
INTRINSIC |
low complexity region
|
1872 |
1891 |
N/A |
INTRINSIC |
Pfam:RYDR_ITPR
|
2120 |
2331 |
3.9e-65 |
PFAM |
low complexity region
|
2372 |
2379 |
N/A |
INTRINSIC |
low complexity region
|
2416 |
2426 |
N/A |
INTRINSIC |
low complexity region
|
2497 |
2510 |
N/A |
INTRINSIC |
Pfam:RyR
|
2699 |
2793 |
1.1e-37 |
PFAM |
Pfam:RyR
|
2819 |
2907 |
9.4e-34 |
PFAM |
PDB:2BCX|B
|
3580 |
3609 |
9e-12 |
PDB |
low complexity region
|
3700 |
3720 |
N/A |
INTRINSIC |
Pfam:RIH_assoc
|
3825 |
3958 |
2.3e-42 |
PFAM |
EFh
|
4026 |
4054 |
1.36e0 |
SMART |
EFh
|
4061 |
4089 |
5.92e1 |
SMART |
low complexity region
|
4218 |
4227 |
N/A |
INTRINSIC |
low complexity region
|
4256 |
4273 |
N/A |
INTRINSIC |
transmembrane domain
|
4278 |
4300 |
N/A |
INTRINSIC |
low complexity region
|
4309 |
4317 |
N/A |
INTRINSIC |
Pfam:RR_TM4-6
|
4332 |
4598 |
5.1e-93 |
PFAM |
Pfam:Ion_trans
|
4705 |
4865 |
9.3e-11 |
PFAM |
|
Predicted Effect |
probably damaging
PolyPhen 2
Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)
(Using ENSMUST00000170156)
|
Predicted Effect |
unknown
|
Predicted Effect |
possibly damaging
PolyPhen 2
Score 0.766 (Sensitivity: 0.85; Specificity: 0.92)
(Using ENSMUST00000221527)
|
Meta Mutation Damage Score |
0.8617 |
Is this an essential gene? |
Essential (E-score: 1.000) |
Phenotypic Category |
Autosomal Semidominant |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(56) : Gene trapped(27) Targeted(29)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00518:Ryr2
|
APN |
13 |
11848978 |
splice site |
probably benign |
|
IGL00757:Ryr2
|
APN |
13 |
11633490 |
splice site |
probably null |
|
IGL00838:Ryr2
|
APN |
13 |
11583389 |
missense |
probably damaging |
0.98 |
IGL00849:Ryr2
|
APN |
13 |
11600364 |
missense |
possibly damaging |
0.91 |
IGL00987:Ryr2
|
APN |
13 |
11750388 |
missense |
probably damaging |
0.99 |
IGL01096:Ryr2
|
APN |
13 |
11718430 |
missense |
probably damaging |
1.00 |
IGL01313:Ryr2
|
APN |
13 |
11653371 |
critical splice acceptor site |
probably null |
|
IGL01349:Ryr2
|
APN |
13 |
11602125 |
missense |
possibly damaging |
0.93 |
IGL01391:Ryr2
|
APN |
13 |
11571571 |
missense |
possibly damaging |
0.96 |
IGL01401:Ryr2
|
APN |
13 |
11606238 |
missense |
possibly damaging |
0.80 |
IGL01412:Ryr2
|
APN |
13 |
11756922 |
missense |
probably benign |
0.10 |
IGL01419:Ryr2
|
APN |
13 |
11814723 |
missense |
possibly damaging |
0.51 |
IGL01432:Ryr2
|
APN |
13 |
11866090 |
missense |
possibly damaging |
0.63 |
IGL01533:Ryr2
|
APN |
13 |
11736676 |
missense |
probably damaging |
1.00 |
IGL01571:Ryr2
|
APN |
13 |
11736647 |
missense |
probably damaging |
1.00 |
IGL01584:Ryr2
|
APN |
13 |
11616644 |
critical splice donor site |
probably null |
|
IGL01611:Ryr2
|
APN |
13 |
11606202 |
missense |
possibly damaging |
0.67 |
IGL01632:Ryr2
|
APN |
13 |
11609854 |
missense |
probably damaging |
0.97 |
IGL01643:Ryr2
|
APN |
13 |
11707563 |
missense |
possibly damaging |
0.94 |
IGL01647:Ryr2
|
APN |
13 |
11600366 |
missense |
probably damaging |
1.00 |
IGL01730:Ryr2
|
APN |
13 |
11616728 |
missense |
possibly damaging |
0.86 |
IGL01834:Ryr2
|
APN |
13 |
11610311 |
missense |
possibly damaging |
0.71 |
IGL01921:Ryr2
|
APN |
13 |
11569436 |
missense |
possibly damaging |
0.96 |
IGL01937:Ryr2
|
APN |
13 |
11805249 |
missense |
probably damaging |
1.00 |
IGL01945:Ryr2
|
APN |
13 |
11805249 |
missense |
probably damaging |
1.00 |
IGL02027:Ryr2
|
APN |
13 |
11611998 |
missense |
probably damaging |
1.00 |
IGL02060:Ryr2
|
APN |
13 |
11762450 |
missense |
probably damaging |
1.00 |
IGL02065:Ryr2
|
APN |
13 |
11587143 |
missense |
possibly damaging |
0.92 |
IGL02084:Ryr2
|
APN |
13 |
11807648 |
nonsense |
probably null |
|
IGL02086:Ryr2
|
APN |
13 |
11750442 |
missense |
probably damaging |
1.00 |
IGL02095:Ryr2
|
APN |
13 |
11774645 |
missense |
probably damaging |
0.98 |
IGL02100:Ryr2
|
APN |
13 |
11752759 |
missense |
possibly damaging |
0.92 |
IGL02122:Ryr2
|
APN |
13 |
11756755 |
missense |
probably damaging |
1.00 |
IGL02202:Ryr2
|
APN |
13 |
11762544 |
splice site |
probably benign |
|
IGL02202:Ryr2
|
APN |
13 |
11745274 |
missense |
probably damaging |
0.97 |
IGL02369:Ryr2
|
APN |
13 |
11634382 |
missense |
possibly damaging |
0.68 |
IGL02383:Ryr2
|
APN |
13 |
11737607 |
splice site |
probably benign |
|
IGL02400:Ryr2
|
APN |
13 |
11620130 |
splice site |
probably benign |
|
IGL02423:Ryr2
|
APN |
13 |
11760084 |
missense |
probably damaging |
1.00 |
IGL02425:Ryr2
|
APN |
13 |
11760560 |
missense |
probably damaging |
0.99 |
IGL02458:Ryr2
|
APN |
13 |
11720585 |
missense |
probably benign |
0.15 |
IGL02602:Ryr2
|
APN |
13 |
11569397 |
utr 3 prime |
probably benign |
|
IGL02694:Ryr2
|
APN |
13 |
11620075 |
missense |
probably damaging |
1.00 |
IGL02726:Ryr2
|
APN |
13 |
11753206 |
missense |
probably damaging |
1.00 |
IGL02747:Ryr2
|
APN |
13 |
11670563 |
missense |
probably damaging |
1.00 |
IGL02795:Ryr2
|
APN |
13 |
11610076 |
missense |
probably benign |
0.21 |
IGL02876:Ryr2
|
APN |
13 |
11722679 |
missense |
probably benign |
0.39 |
IGL02878:Ryr2
|
APN |
13 |
11933205 |
missense |
probably benign |
0.10 |
IGL02887:Ryr2
|
APN |
13 |
11606155 |
missense |
probably damaging |
0.97 |
IGL02926:Ryr2
|
APN |
13 |
11774721 |
missense |
probably damaging |
0.99 |
IGL03030:Ryr2
|
APN |
13 |
11699365 |
missense |
probably damaging |
0.99 |
IGL03064:Ryr2
|
APN |
13 |
11658788 |
critical splice acceptor site |
probably null |
|
IGL03102:Ryr2
|
APN |
13 |
11650468 |
splice site |
probably benign |
|
IGL03152:Ryr2
|
APN |
13 |
11868036 |
missense |
probably damaging |
1.00 |
IGL03176:Ryr2
|
APN |
13 |
11756909 |
nonsense |
probably null |
|
IGL03180:Ryr2
|
APN |
13 |
11583449 |
missense |
possibly damaging |
0.95 |
IGL03213:Ryr2
|
APN |
13 |
11739273 |
splice site |
probably benign |
|
IGL03390:Ryr2
|
APN |
13 |
11787302 |
missense |
probably benign |
|
IGL03410:Ryr2
|
APN |
13 |
11603033 |
missense |
probably damaging |
0.99 |
Arruda2
|
UTSW |
13 |
11894382 |
missense |
probably damaging |
1.00 |
Arruda3
|
UTSW |
13 |
11570334 |
missense |
possibly damaging |
0.91 |
barricuda
|
UTSW |
13 |
11609900 |
missense |
probably benign |
0.06 |
BB006:Ryr2
|
UTSW |
13 |
11705181 |
nonsense |
probably null |
|
BB006:Ryr2
|
UTSW |
13 |
11609680 |
missense |
probably damaging |
1.00 |
BB016:Ryr2
|
UTSW |
13 |
11705181 |
nonsense |
probably null |
|
BB016:Ryr2
|
UTSW |
13 |
11609680 |
missense |
probably damaging |
1.00 |
H8562:Ryr2
|
UTSW |
13 |
11732027 |
splice site |
probably benign |
|
IGL02799:Ryr2
|
UTSW |
13 |
11680848 |
missense |
probably damaging |
1.00 |
IGL02991:Ryr2
|
UTSW |
13 |
11776192 |
missense |
probably damaging |
0.99 |
PIT4142001:Ryr2
|
UTSW |
13 |
11722682 |
missense |
probably damaging |
0.97 |
PIT4260001:Ryr2
|
UTSW |
13 |
11609641 |
missense |
possibly damaging |
0.93 |
PIT4458001:Ryr2
|
UTSW |
13 |
11570334 |
missense |
probably benign |
0.29 |
R0003:Ryr2
|
UTSW |
13 |
11839265 |
missense |
probably damaging |
1.00 |
R0004:Ryr2
|
UTSW |
13 |
11680805 |
missense |
probably benign |
|
R0018:Ryr2
|
UTSW |
13 |
11610109 |
missense |
possibly damaging |
0.94 |
R0048:Ryr2
|
UTSW |
13 |
11610670 |
missense |
probably damaging |
1.00 |
R0048:Ryr2
|
UTSW |
13 |
11610670 |
missense |
probably damaging |
1.00 |
R0056:Ryr2
|
UTSW |
13 |
11683924 |
missense |
probably damaging |
0.97 |
R0062:Ryr2
|
UTSW |
13 |
11884002 |
critical splice donor site |
probably null |
|
R0062:Ryr2
|
UTSW |
13 |
11884002 |
critical splice donor site |
probably null |
|
R0080:Ryr2
|
UTSW |
13 |
11583361 |
missense |
probably damaging |
0.98 |
R0116:Ryr2
|
UTSW |
13 |
11724807 |
missense |
probably damaging |
1.00 |
R0148:Ryr2
|
UTSW |
13 |
11729434 |
missense |
probably damaging |
1.00 |
R0206:Ryr2
|
UTSW |
13 |
11691137 |
splice site |
probably benign |
|
R0226:Ryr2
|
UTSW |
13 |
11787442 |
missense |
probably damaging |
1.00 |
R0285:Ryr2
|
UTSW |
13 |
11731863 |
missense |
probably damaging |
1.00 |
R0365:Ryr2
|
UTSW |
13 |
11683725 |
missense |
possibly damaging |
0.90 |
R0401:Ryr2
|
UTSW |
13 |
11720570 |
missense |
probably benign |
0.45 |
R0415:Ryr2
|
UTSW |
13 |
11884042 |
missense |
probably damaging |
0.97 |
R0418:Ryr2
|
UTSW |
13 |
11848981 |
splice site |
probably benign |
|
R0558:Ryr2
|
UTSW |
13 |
11814747 |
missense |
probably damaging |
1.00 |
R0558:Ryr2
|
UTSW |
13 |
11653329 |
missense |
probably damaging |
1.00 |
R0574:Ryr2
|
UTSW |
13 |
11746555 |
missense |
probably benign |
0.02 |
R0586:Ryr2
|
UTSW |
13 |
11650445 |
missense |
probably null |
|
R0601:Ryr2
|
UTSW |
13 |
11720519 |
critical splice donor site |
probably null |
|
R0610:Ryr2
|
UTSW |
13 |
11637838 |
missense |
probably damaging |
1.00 |
R0648:Ryr2
|
UTSW |
13 |
11739219 |
missense |
possibly damaging |
0.86 |
R0727:Ryr2
|
UTSW |
13 |
11581771 |
missense |
probably damaging |
1.00 |
R0743:Ryr2
|
UTSW |
13 |
11569415 |
missense |
probably damaging |
0.99 |
R0821:Ryr2
|
UTSW |
13 |
11753012 |
missense |
probably benign |
0.35 |
R0884:Ryr2
|
UTSW |
13 |
11569415 |
missense |
probably damaging |
0.99 |
R1104:Ryr2
|
UTSW |
13 |
11684855 |
missense |
probably damaging |
0.99 |
R1114:Ryr2
|
UTSW |
13 |
11960867 |
missense |
probably damaging |
0.98 |
R1167:Ryr2
|
UTSW |
13 |
11674999 |
missense |
possibly damaging |
0.94 |
R1238:Ryr2
|
UTSW |
13 |
11774589 |
missense |
probably damaging |
1.00 |
R1239:Ryr2
|
UTSW |
13 |
11897929 |
critical splice donor site |
probably null |
|
R1296:Ryr2
|
UTSW |
13 |
11702765 |
splice site |
probably benign |
|
R1400:Ryr2
|
UTSW |
13 |
11609962 |
missense |
probably benign |
0.08 |
R1439:Ryr2
|
UTSW |
13 |
11729389 |
splice site |
probably benign |
|
R1443:Ryr2
|
UTSW |
13 |
11794152 |
missense |
probably benign |
0.19 |
R1446:Ryr2
|
UTSW |
13 |
11753035 |
missense |
probably benign |
0.09 |
R1458:Ryr2
|
UTSW |
13 |
11741908 |
missense |
probably damaging |
0.97 |
R1497:Ryr2
|
UTSW |
13 |
11616727 |
missense |
probably damaging |
0.99 |
R1505:Ryr2
|
UTSW |
13 |
11569478 |
missense |
possibly damaging |
0.84 |
R1548:Ryr2
|
UTSW |
13 |
11569435 |
nonsense |
probably null |
|
R1551:Ryr2
|
UTSW |
13 |
11800029 |
critical splice acceptor site |
probably null |
|
R1567:Ryr2
|
UTSW |
13 |
11774563 |
missense |
possibly damaging |
0.87 |
R1581:Ryr2
|
UTSW |
13 |
11809449 |
missense |
probably benign |
0.01 |
R1645:Ryr2
|
UTSW |
13 |
11733368 |
nonsense |
probably null |
|
R1686:Ryr2
|
UTSW |
13 |
11618665 |
splice site |
probably benign |
|
R1696:Ryr2
|
UTSW |
13 |
11746543 |
missense |
probably benign |
0.02 |
R1708:Ryr2
|
UTSW |
13 |
11602328 |
splice site |
probably null |
|
R1728:Ryr2
|
UTSW |
13 |
11602308 |
missense |
possibly damaging |
0.94 |
R1745:Ryr2
|
UTSW |
13 |
11805153 |
missense |
probably damaging |
1.00 |
R1771:Ryr2
|
UTSW |
13 |
11760062 |
critical splice donor site |
probably null |
|
R1776:Ryr2
|
UTSW |
13 |
11760062 |
critical splice donor site |
probably null |
|
R1783:Ryr2
|
UTSW |
13 |
11715257 |
nonsense |
probably null |
|
R1801:Ryr2
|
UTSW |
13 |
11610167 |
missense |
probably benign |
0.01 |
R1812:Ryr2
|
UTSW |
13 |
11575472 |
missense |
probably damaging |
0.97 |
R1820:Ryr2
|
UTSW |
13 |
11602202 |
missense |
probably damaging |
0.99 |
R1835:Ryr2
|
UTSW |
13 |
11784764 |
missense |
probably benign |
0.06 |
R1868:Ryr2
|
UTSW |
13 |
11746586 |
missense |
probably benign |
0.02 |
R1869:Ryr2
|
UTSW |
13 |
11676961 |
missense |
probably damaging |
0.98 |
R1884:Ryr2
|
UTSW |
13 |
11753242 |
missense |
probably damaging |
0.97 |
R1892:Ryr2
|
UTSW |
13 |
11673844 |
nonsense |
probably null |
|
R1897:Ryr2
|
UTSW |
13 |
11765818 |
missense |
probably benign |
0.09 |
R1899:Ryr2
|
UTSW |
13 |
11606222 |
missense |
probably benign |
|
R1909:Ryr2
|
UTSW |
13 |
11715235 |
missense |
probably damaging |
1.00 |
R1918:Ryr2
|
UTSW |
13 |
11571584 |
missense |
possibly damaging |
0.91 |
R1937:Ryr2
|
UTSW |
13 |
11683848 |
missense |
probably damaging |
1.00 |
R1943:Ryr2
|
UTSW |
13 |
11746609 |
missense |
probably benign |
0.10 |
R1956:Ryr2
|
UTSW |
13 |
11695966 |
missense |
probably damaging |
1.00 |
R1983:Ryr2
|
UTSW |
13 |
11600288 |
splice site |
probably null |
|
R2018:Ryr2
|
UTSW |
13 |
11866074 |
missense |
possibly damaging |
0.59 |
R2019:Ryr2
|
UTSW |
13 |
11866074 |
missense |
possibly damaging |
0.59 |
R2060:Ryr2
|
UTSW |
13 |
11610622 |
missense |
probably damaging |
1.00 |
R2061:Ryr2
|
UTSW |
13 |
11680764 |
splice site |
probably null |
|
R2088:Ryr2
|
UTSW |
13 |
11677115 |
missense |
probably benign |
0.04 |
R2089:Ryr2
|
UTSW |
13 |
11960863 |
missense |
probably benign |
0.23 |
R2091:Ryr2
|
UTSW |
13 |
11960863 |
missense |
probably benign |
0.23 |
R2091:Ryr2
|
UTSW |
13 |
11960863 |
missense |
probably benign |
0.23 |
R2127:Ryr2
|
UTSW |
13 |
11727081 |
missense |
probably damaging |
1.00 |
R2140:Ryr2
|
UTSW |
13 |
11575493 |
missense |
probably damaging |
1.00 |
R2153:Ryr2
|
UTSW |
13 |
11592759 |
missense |
possibly damaging |
0.86 |
R2179:Ryr2
|
UTSW |
13 |
11720679 |
nonsense |
probably null |
|
R2207:Ryr2
|
UTSW |
13 |
11825823 |
missense |
probably damaging |
1.00 |
R2237:Ryr2
|
UTSW |
13 |
11677146 |
missense |
probably benign |
0.18 |
R2258:Ryr2
|
UTSW |
13 |
11753102 |
missense |
possibly damaging |
0.94 |
R2312:Ryr2
|
UTSW |
13 |
11753128 |
missense |
probably damaging |
1.00 |
R2421:Ryr2
|
UTSW |
13 |
11606123 |
missense |
probably damaging |
0.98 |
R2438:Ryr2
|
UTSW |
13 |
11816734 |
missense |
probably damaging |
1.00 |
R2483:Ryr2
|
UTSW |
13 |
11774589 |
missense |
probably damaging |
1.00 |
R2860:Ryr2
|
UTSW |
13 |
11607979 |
missense |
probably damaging |
0.98 |
R2861:Ryr2
|
UTSW |
13 |
11607979 |
missense |
probably damaging |
0.98 |
R2867:Ryr2
|
UTSW |
13 |
11776235 |
missense |
probably damaging |
1.00 |
R2867:Ryr2
|
UTSW |
13 |
11776235 |
missense |
probably damaging |
1.00 |
R3618:Ryr2
|
UTSW |
13 |
11787466 |
critical splice acceptor site |
probably null |
|
R3876:Ryr2
|
UTSW |
13 |
11603045 |
missense |
probably damaging |
0.99 |
R3906:Ryr2
|
UTSW |
13 |
11753095 |
missense |
possibly damaging |
0.87 |
R3912:Ryr2
|
UTSW |
13 |
11787313 |
missense |
probably damaging |
0.99 |
R4018:Ryr2
|
UTSW |
13 |
11933300 |
missense |
probably damaging |
1.00 |
R4114:Ryr2
|
UTSW |
13 |
11707568 |
missense |
probably damaging |
1.00 |
R4119:Ryr2
|
UTSW |
13 |
11794153 |
missense |
probably benign |
0.22 |
R4127:Ryr2
|
UTSW |
13 |
11602323 |
missense |
possibly damaging |
0.91 |
R4222:Ryr2
|
UTSW |
13 |
11752759 |
missense |
possibly damaging |
0.92 |
R4233:Ryr2
|
UTSW |
13 |
11765611 |
missense |
probably benign |
0.20 |
R4355:Ryr2
|
UTSW |
13 |
11664698 |
missense |
probably benign |
0.05 |
R4384:Ryr2
|
UTSW |
13 |
11620119 |
missense |
probably damaging |
0.99 |
R4422:Ryr2
|
UTSW |
13 |
11731952 |
nonsense |
probably null |
|
R4430:Ryr2
|
UTSW |
13 |
11750413 |
missense |
probably damaging |
0.98 |
R4624:Ryr2
|
UTSW |
13 |
12121301 |
missense |
possibly damaging |
0.47 |
R4663:Ryr2
|
UTSW |
13 |
11764395 |
missense |
possibly damaging |
0.47 |
R4665:Ryr2
|
UTSW |
13 |
11765571 |
splice site |
probably null |
|
R4668:Ryr2
|
UTSW |
13 |
11608003 |
missense |
probably benign |
|
R4677:Ryr2
|
UTSW |
13 |
11721553 |
missense |
probably damaging |
0.98 |
R4679:Ryr2
|
UTSW |
13 |
11839255 |
missense |
probably benign |
0.34 |
R4680:Ryr2
|
UTSW |
13 |
11610119 |
missense |
probably benign |
0.04 |
R4685:Ryr2
|
UTSW |
13 |
11707532 |
missense |
probably damaging |
1.00 |
R4709:Ryr2
|
UTSW |
13 |
11731884 |
missense |
probably damaging |
1.00 |
R4731:Ryr2
|
UTSW |
13 |
11592795 |
missense |
possibly damaging |
0.53 |
R4732:Ryr2
|
UTSW |
13 |
11592795 |
missense |
possibly damaging |
0.53 |
R4733:Ryr2
|
UTSW |
13 |
11592795 |
missense |
possibly damaging |
0.53 |
R4734:Ryr2
|
UTSW |
13 |
11752639 |
missense |
probably damaging |
0.99 |
R4740:Ryr2
|
UTSW |
13 |
11671933 |
missense |
possibly damaging |
0.95 |
R4801:Ryr2
|
UTSW |
13 |
11702818 |
missense |
probably damaging |
1.00 |
R4801:Ryr2
|
UTSW |
13 |
11723113 |
missense |
probably damaging |
1.00 |
R4802:Ryr2
|
UTSW |
13 |
11702818 |
missense |
probably damaging |
1.00 |
R4802:Ryr2
|
UTSW |
13 |
11723113 |
missense |
probably damaging |
1.00 |
R4804:Ryr2
|
UTSW |
13 |
11731983 |
missense |
probably damaging |
1.00 |
R4811:Ryr2
|
UTSW |
13 |
11670584 |
missense |
probably damaging |
0.97 |
R4850:Ryr2
|
UTSW |
13 |
11760638 |
missense |
probably damaging |
1.00 |
R4850:Ryr2
|
UTSW |
13 |
11683706 |
missense |
probably damaging |
0.99 |
R4880:Ryr2
|
UTSW |
13 |
11767104 |
missense |
probably damaging |
1.00 |
R4917:Ryr2
|
UTSW |
13 |
11609872 |
missense |
probably damaging |
0.96 |
R4918:Ryr2
|
UTSW |
13 |
11609872 |
missense |
probably damaging |
0.96 |
R4922:Ryr2
|
UTSW |
13 |
11724849 |
missense |
probably damaging |
0.99 |
R4933:Ryr2
|
UTSW |
13 |
11960831 |
missense |
probably damaging |
0.96 |
R4950:Ryr2
|
UTSW |
13 |
11756897 |
missense |
probably damaging |
1.00 |
R4957:Ryr2
|
UTSW |
13 |
11799966 |
missense |
probably damaging |
0.97 |
R4964:Ryr2
|
UTSW |
13 |
11848878 |
missense |
probably benign |
0.00 |
R4964:Ryr2
|
UTSW |
13 |
11729497 |
missense |
possibly damaging |
0.49 |
R4966:Ryr2
|
UTSW |
13 |
11729497 |
missense |
possibly damaging |
0.49 |
R4966:Ryr2
|
UTSW |
13 |
11848878 |
missense |
probably benign |
0.00 |
R4997:Ryr2
|
UTSW |
13 |
11610192 |
missense |
probably benign |
0.09 |
R4998:Ryr2
|
UTSW |
13 |
11658781 |
missense |
probably damaging |
1.00 |
R5033:Ryr2
|
UTSW |
13 |
11602140 |
missense |
possibly damaging |
0.93 |
R5061:Ryr2
|
UTSW |
13 |
11650422 |
missense |
possibly damaging |
0.74 |
R5062:Ryr2
|
UTSW |
13 |
11715240 |
missense |
probably damaging |
0.97 |
R5088:Ryr2
|
UTSW |
13 |
11727129 |
nonsense |
probably null |
|
R5135:Ryr2
|
UTSW |
13 |
11677016 |
missense |
probably benign |
0.05 |
R5138:Ryr2
|
UTSW |
13 |
11675175 |
missense |
probably damaging |
1.00 |
R5168:Ryr2
|
UTSW |
13 |
11767207 |
missense |
probably benign |
|
R5187:Ryr2
|
UTSW |
13 |
11787338 |
missense |
probably damaging |
0.99 |
R5197:Ryr2
|
UTSW |
13 |
11653316 |
critical splice donor site |
probably null |
|
R5262:Ryr2
|
UTSW |
13 |
11787323 |
missense |
probably damaging |
0.99 |
R5325:Ryr2
|
UTSW |
13 |
11705249 |
missense |
probably damaging |
0.97 |
R5381:Ryr2
|
UTSW |
13 |
11571544 |
missense |
probably damaging |
1.00 |
R5437:Ryr2
|
UTSW |
13 |
11670599 |
missense |
probably damaging |
1.00 |
R5477:Ryr2
|
UTSW |
13 |
11720542 |
missense |
probably damaging |
1.00 |
R5497:Ryr2
|
UTSW |
13 |
11720587 |
missense |
probably null |
0.15 |
R5509:Ryr2
|
UTSW |
13 |
11760487 |
missense |
probably damaging |
0.98 |
R5518:Ryr2
|
UTSW |
13 |
11702795 |
missense |
probably benign |
0.01 |
R5571:Ryr2
|
UTSW |
13 |
11570334 |
missense |
possibly damaging |
0.91 |
R5591:Ryr2
|
UTSW |
13 |
11609900 |
missense |
probably benign |
0.06 |
R5619:Ryr2
|
UTSW |
13 |
11723088 |
missense |
probably damaging |
1.00 |
R5630:Ryr2
|
UTSW |
13 |
11616691 |
missense |
probably damaging |
1.00 |
R5644:Ryr2
|
UTSW |
13 |
11610468 |
missense |
probably damaging |
0.99 |
R5667:Ryr2
|
UTSW |
13 |
11774722 |
missense |
probably damaging |
1.00 |
R5775:Ryr2
|
UTSW |
13 |
11784848 |
missense |
probably damaging |
1.00 |
R5836:Ryr2
|
UTSW |
13 |
11618618 |
missense |
probably damaging |
1.00 |
R5858:Ryr2
|
UTSW |
13 |
11575460 |
missense |
probably damaging |
0.99 |
R5934:Ryr2
|
UTSW |
13 |
11599040 |
missense |
probably damaging |
0.96 |
R5939:Ryr2
|
UTSW |
13 |
11805218 |
missense |
probably damaging |
0.99 |
R5941:Ryr2
|
UTSW |
13 |
11702788 |
missense |
probably damaging |
1.00 |
R5945:Ryr2
|
UTSW |
13 |
11675008 |
missense |
probably damaging |
1.00 |
R5946:Ryr2
|
UTSW |
13 |
11741839 |
missense |
probably damaging |
1.00 |
R5966:Ryr2
|
UTSW |
13 |
11677124 |
nonsense |
probably null |
|
R5974:Ryr2
|
UTSW |
13 |
11729397 |
splice site |
probably null |
|
R6104:Ryr2
|
UTSW |
13 |
11814711 |
missense |
probably damaging |
1.00 |
R6118:Ryr2
|
UTSW |
13 |
11807575 |
missense |
possibly damaging |
0.69 |
R6149:Ryr2
|
UTSW |
13 |
11683903 |
missense |
probably benign |
|
R6208:Ryr2
|
UTSW |
13 |
11910106 |
missense |
probably benign |
0.04 |
R6217:Ryr2
|
UTSW |
13 |
11848964 |
missense |
probably damaging |
1.00 |
R6230:Ryr2
|
UTSW |
13 |
11674993 |
missense |
probably damaging |
0.99 |
R6279:Ryr2
|
UTSW |
13 |
11695885 |
missense |
probably damaging |
0.97 |
R6294:Ryr2
|
UTSW |
13 |
11894382 |
missense |
probably damaging |
1.00 |
R6300:Ryr2
|
UTSW |
13 |
11695885 |
missense |
probably damaging |
0.97 |
R6350:Ryr2
|
UTSW |
13 |
11776282 |
missense |
probably damaging |
0.98 |
R6484:Ryr2
|
UTSW |
13 |
11677269 |
missense |
possibly damaging |
0.90 |
R6489:Ryr2
|
UTSW |
13 |
11848893 |
missense |
probably benign |
0.29 |
R6548:Ryr2
|
UTSW |
13 |
11683707 |
missense |
probably damaging |
1.00 |
R6591:Ryr2
|
UTSW |
13 |
11609609 |
missense |
probably benign |
0.01 |
R6623:Ryr2
|
UTSW |
13 |
11724951 |
missense |
probably damaging |
1.00 |
R6649:Ryr2
|
UTSW |
13 |
11610529 |
missense |
probably damaging |
0.99 |
R6691:Ryr2
|
UTSW |
13 |
11609609 |
missense |
probably benign |
0.01 |
R6770:Ryr2
|
UTSW |
13 |
11753348 |
missense |
probably damaging |
1.00 |
R6802:Ryr2
|
UTSW |
13 |
11701852 |
missense |
probably damaging |
1.00 |
R6809:Ryr2
|
UTSW |
13 |
11741816 |
missense |
probably damaging |
1.00 |
R6893:Ryr2
|
UTSW |
13 |
11844540 |
missense |
possibly damaging |
0.75 |
R6911:Ryr2
|
UTSW |
13 |
11842445 |
missense |
possibly damaging |
0.50 |
R6915:Ryr2
|
UTSW |
13 |
11760487 |
missense |
probably damaging |
1.00 |
R6943:Ryr2
|
UTSW |
13 |
11581834 |
missense |
possibly damaging |
0.92 |
R6960:Ryr2
|
UTSW |
13 |
11816129 |
missense |
probably benign |
0.28 |
R6997:Ryr2
|
UTSW |
13 |
11669266 |
missense |
possibly damaging |
0.88 |
R6998:Ryr2
|
UTSW |
13 |
11727052 |
missense |
probably damaging |
0.99 |
R7001:Ryr2
|
UTSW |
13 |
11809491 |
missense |
probably damaging |
0.98 |
R7047:Ryr2
|
UTSW |
13 |
11839286 |
missense |
possibly damaging |
0.64 |
R7089:Ryr2
|
UTSW |
13 |
11664662 |
missense |
probably benign |
0.10 |
R7125:Ryr2
|
UTSW |
13 |
11684873 |
missense |
probably damaging |
0.99 |
R7127:Ryr2
|
UTSW |
13 |
11670599 |
missense |
probably damaging |
1.00 |
R7131:Ryr2
|
UTSW |
13 |
11683697 |
critical splice donor site |
probably null |
|
R7131:Ryr2
|
UTSW |
13 |
11655213 |
missense |
possibly damaging |
0.63 |
R7159:Ryr2
|
UTSW |
13 |
11825794 |
missense |
probably damaging |
0.99 |
R7174:Ryr2
|
UTSW |
13 |
11816063 |
missense |
possibly damaging |
0.81 |
R7180:Ryr2
|
UTSW |
13 |
11701864 |
missense |
probably damaging |
1.00 |
R7182:Ryr2
|
UTSW |
13 |
11774643 |
missense |
probably benign |
|
R7189:Ryr2
|
UTSW |
13 |
11898009 |
missense |
probably damaging |
1.00 |
R7241:Ryr2
|
UTSW |
13 |
11680799 |
missense |
possibly damaging |
0.71 |
R7244:Ryr2
|
UTSW |
13 |
11612032 |
missense |
probably damaging |
1.00 |
R7326:Ryr2
|
UTSW |
13 |
11753080 |
missense |
possibly damaging |
0.95 |
R7331:Ryr2
|
UTSW |
13 |
11760517 |
missense |
probably benign |
|
R7365:Ryr2
|
UTSW |
13 |
11655161 |
missense |
probably damaging |
0.99 |
R7372:Ryr2
|
UTSW |
13 |
11695885 |
missense |
probably damaging |
0.97 |
R7395:Ryr2
|
UTSW |
13 |
11799997 |
missense |
probably damaging |
0.98 |
R7404:Ryr2
|
UTSW |
13 |
11750506 |
missense |
probably damaging |
0.97 |
R7417:Ryr2
|
UTSW |
13 |
11571634 |
splice site |
probably null |
|
R7425:Ryr2
|
UTSW |
13 |
11720530 |
missense |
probably benign |
0.20 |
R7444:Ryr2
|
UTSW |
13 |
11570349 |
missense |
probably benign |
0.25 |
R7456:Ryr2
|
UTSW |
13 |
11767168 |
missense |
probably benign |
|
R7460:Ryr2
|
UTSW |
13 |
11720596 |
missense |
probably benign |
0.10 |
R7474:Ryr2
|
UTSW |
13 |
11609762 |
missense |
probably benign |
0.04 |
R7543:Ryr2
|
UTSW |
13 |
11653317 |
critical splice donor site |
probably null |
|
R7549:Ryr2
|
UTSW |
13 |
11752871 |
missense |
probably benign |
0.15 |
R7558:Ryr2
|
UTSW |
13 |
11814711 |
missense |
probably damaging |
1.00 |
R7565:Ryr2
|
UTSW |
13 |
11575539 |
missense |
possibly damaging |
0.84 |
R7627:Ryr2
|
UTSW |
13 |
11776213 |
missense |
possibly damaging |
0.65 |
R7698:Ryr2
|
UTSW |
13 |
11776201 |
missense |
possibly damaging |
0.94 |
R7702:Ryr2
|
UTSW |
13 |
11705219 |
missense |
probably damaging |
0.99 |
R7719:Ryr2
|
UTSW |
13 |
11745229 |
missense |
possibly damaging |
0.94 |
R7772:Ryr2
|
UTSW |
13 |
11765897 |
missense |
probably benign |
|
R7797:Ryr2
|
UTSW |
13 |
11816066 |
missense |
probably damaging |
0.99 |
R7829:Ryr2
|
UTSW |
13 |
11842493 |
missense |
possibly damaging |
0.81 |
R7855:Ryr2
|
UTSW |
13 |
11721509 |
nonsense |
probably null |
|
R7872:Ryr2
|
UTSW |
13 |
11610610 |
missense |
probably damaging |
1.00 |
R7908:Ryr2
|
UTSW |
13 |
11807634 |
missense |
probably benign |
0.01 |
R7929:Ryr2
|
UTSW |
13 |
11609680 |
missense |
probably damaging |
1.00 |
R7929:Ryr2
|
UTSW |
13 |
11705181 |
nonsense |
probably null |
|
R7952:Ryr2
|
UTSW |
13 |
11661313 |
splice site |
probably null |
|
R8008:Ryr2
|
UTSW |
13 |
11671980 |
missense |
probably benign |
0.30 |
R8011:Ryr2
|
UTSW |
13 |
11603026 |
critical splice donor site |
probably null |
|
R8097:Ryr2
|
UTSW |
13 |
11960881 |
missense |
probably damaging |
0.98 |
R8133:Ryr2
|
UTSW |
13 |
11618584 |
missense |
probably damaging |
1.00 |
R8253:Ryr2
|
UTSW |
13 |
11842439 |
missense |
possibly damaging |
0.94 |
R8278:Ryr2
|
UTSW |
13 |
11610392 |
nonsense |
probably null |
|
R8351:Ryr2
|
UTSW |
13 |
11814718 |
missense |
probably damaging |
0.98 |
R8401:Ryr2
|
UTSW |
13 |
11683821 |
missense |
possibly damaging |
0.95 |
R8403:Ryr2
|
UTSW |
13 |
11699364 |
missense |
possibly damaging |
0.95 |
R8431:Ryr2
|
UTSW |
13 |
11673894 |
missense |
probably benign |
0.00 |
R8509:Ryr2
|
UTSW |
13 |
11592664 |
critical splice donor site |
probably null |
|
R8551:Ryr2
|
UTSW |
13 |
11575479 |
missense |
possibly damaging |
0.93 |
R8684:Ryr2
|
UTSW |
13 |
11702875 |
missense |
probably damaging |
0.99 |
R8735:Ryr2
|
UTSW |
13 |
11701833 |
missense |
probably damaging |
0.97 |
R8766:Ryr2
|
UTSW |
13 |
11683855 |
missense |
probably damaging |
0.97 |
R8817:Ryr2
|
UTSW |
13 |
11750509 |
missense |
possibly damaging |
0.95 |
R8827:Ryr2
|
UTSW |
13 |
11572934 |
missense |
possibly damaging |
0.80 |
R8884:Ryr2
|
UTSW |
13 |
11794152 |
missense |
probably benign |
0.19 |
R8889:Ryr2
|
UTSW |
13 |
11799990 |
missense |
probably damaging |
0.99 |
R8891:Ryr2
|
UTSW |
13 |
11814768 |
missense |
probably damaging |
1.00 |
R8979:Ryr2
|
UTSW |
13 |
11609924 |
missense |
probably benign |
0.00 |
R9013:Ryr2
|
UTSW |
13 |
11618618 |
missense |
probably damaging |
0.98 |
R9040:Ryr2
|
UTSW |
13 |
11609672 |
missense |
probably damaging |
0.97 |
R9044:Ryr2
|
UTSW |
13 |
11752989 |
nonsense |
probably null |
|
R9056:Ryr2
|
UTSW |
13 |
11610817 |
missense |
possibly damaging |
0.94 |
R9084:Ryr2
|
UTSW |
13 |
11616724 |
missense |
probably damaging |
1.00 |
R9113:Ryr2
|
UTSW |
13 |
11618741 |
intron |
probably benign |
|
R9116:Ryr2
|
UTSW |
13 |
11587185 |
missense |
possibly damaging |
0.93 |
R9125:Ryr2
|
UTSW |
13 |
11669292 |
missense |
probably benign |
0.28 |
R9148:Ryr2
|
UTSW |
13 |
11900424 |
missense |
probably benign |
0.02 |
R9210:Ryr2
|
UTSW |
13 |
11844560 |
missense |
probably damaging |
0.99 |
R9212:Ryr2
|
UTSW |
13 |
11844560 |
missense |
probably damaging |
0.99 |
R9233:Ryr2
|
UTSW |
13 |
11610772 |
missense |
possibly damaging |
0.77 |
R9254:Ryr2
|
UTSW |
13 |
11898002 |
missense |
probably damaging |
1.00 |
R9262:Ryr2
|
UTSW |
13 |
11765854 |
missense |
probably damaging |
0.97 |
R9275:Ryr2
|
UTSW |
13 |
11897976 |
missense |
probably benign |
0.10 |
R9278:Ryr2
|
UTSW |
13 |
11897976 |
missense |
probably benign |
0.10 |
R9309:Ryr2
|
UTSW |
13 |
11721578 |
missense |
probably damaging |
0.99 |
R9379:Ryr2
|
UTSW |
13 |
11898002 |
missense |
probably damaging |
1.00 |
R9409:Ryr2
|
UTSW |
13 |
11695973 |
missense |
probably damaging |
0.99 |
R9429:Ryr2
|
UTSW |
13 |
11809459 |
missense |
probably damaging |
0.97 |
R9445:Ryr2
|
UTSW |
13 |
11787463 |
missense |
probably damaging |
1.00 |
R9464:Ryr2
|
UTSW |
13 |
11752680 |
missense |
probably benign |
0.00 |
R9467:Ryr2
|
UTSW |
13 |
11571490 |
missense |
possibly damaging |
0.70 |
R9546:Ryr2
|
UTSW |
13 |
11602101 |
critical splice donor site |
probably null |
|
R9562:Ryr2
|
UTSW |
13 |
11760104 |
missense |
probably damaging |
1.00 |
R9609:Ryr2
|
UTSW |
13 |
11683848 |
missense |
probably damaging |
1.00 |
R9704:Ryr2
|
UTSW |
13 |
11737646 |
missense |
probably damaging |
1.00 |
R9764:Ryr2
|
UTSW |
13 |
11701935 |
missense |
possibly damaging |
0.67 |
R9772:Ryr2
|
UTSW |
13 |
11609785 |
missense |
probably benign |
0.13 |
R9776:Ryr2
|
UTSW |
13 |
11707599 |
missense |
probably damaging |
0.98 |
S24628:Ryr2
|
UTSW |
13 |
11884042 |
missense |
probably damaging |
0.97 |
X0019:Ryr2
|
UTSW |
13 |
11718387 |
missense |
probably benign |
0.04 |
Z1176:Ryr2
|
UTSW |
13 |
11658689 |
critical splice donor site |
probably null |
|
Z1176:Ryr2
|
UTSW |
13 |
11613497 |
critical splice acceptor site |
probably null |
|
Z1176:Ryr2
|
UTSW |
13 |
11809435 |
nonsense |
probably null |
|
Z1177:Ryr2
|
UTSW |
13 |
11765759 |
missense |
possibly damaging |
0.87 |
|
Mode of Inheritance |
Autosomal Semidominant |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:40 PM
by Anne Murray
|
Record Created |
2017-03-07 3:29 PM
|
Record Posted |
2018-10-24 |
Phenotypic Description |
The Arruda phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4998, some of which showed an increase in the average heart rate (Figure 1).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 92 mutations. The heart rate phenotype was linked by continuous variable mapping to a mutation in Ryr2: a G to A transition at base pair 11,643,895 (v38) on chromosome 13, or base pair 463,051 in the GenBank genomic region NC_000079 encoding Ryr2. Linkage was found with an additive model of inheritance, wherein eight variant homozygotes and 23 heterozygous mice departed phenotypically from 20 homozygous reference mice with a P value of 3.858 x 10-5 (Figure 2). The mutation corresponds to residue 11,340 in the mRNA sequence NM_023868 within exon 77 of 105 total exons.
11324 AATCTGCCAAGGCATCGGGCGGTCAATCTTTTT
3609 -N--L--P--R--H--R--A--V--N--L--F-
|
The mutated nucleotide is indicated in red. The mutation results in an arginine (R) to glutamine (Q) substitution at position 3,614 (R3614Q) in the Ryr2 protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 0.491). |
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
Ryr2 encodes cardiac ryanodine receptor 2 (RYR2), one of three RYRs (i.e., RYR1, RYR2, and RYR3). RYR1 is the major RYR form found in skeletal muscle (1), RYR2 is the major form in cardiac muscle, and RYR3 is more widely expressed with high levels in the brain; the function of RYR3 is unknown (2). The three isoforms share approximately 66% sequence identity, but each RYR exhibits different Ca2+ binding affinities with RyR1 > RyR2 > RyR3. Functional RYRs are homotetramers that form a pore. Each monomer has a large cytoplasmic N-terminal tail, six transmembrane domains, and a short C-terminal tail (Figure 3). The cytoplasmic tail of RYR2 consists of an N-terminal domain (NTD), three SPRY (SpIa and RYR) domains, four armadillo repeat-containing domains (termed the Handle domain), five MIR (Mannosyltransferase, Inositol 1,4,5-trisphosphate receptor, and Ryanodine receptor) domains, two RYR domains (alternatively P1 and P2 domains), three leucine zippers, and two putative EF-hand motifs (3-7). The NTD contains three subdomains: A (alternatively, Pfam domain: Ins145_P3_rec; amino acids 1 to 217), B (alternatively, Pfam domain: MIR; amino acids 218 to 409), and C (alternatively, Pfam domain: RIH; amino acids 410 to 543) (6;8). Overall, the NTD is not required for channel gating (7); however, subdomain A is involved in channel termination, subdomain B functions in channel suppression, and subdomain C functions in channel activation and RYR2 expression (7). SPRY domains are found in members of the immunoglobulin superfamily; the function of SPRY domains is unknown. MIR domains are found in protein O-mannosyltransferases, inositol trisphosphate receptors, and RYR proteins. The MIR domains putatively participate in the structure of the clamp domain (9). The P1 domain is a component of the clamp, while the P2 domain contains the Ser2808 and Ser2814 phosphorylation sites. The leucine zippers function as specific anchoring sites for muscle A-kinase-anchoring protein (mAKAP), spinophilin, and PR130, which regulates RYR2 phosphorylation (10). The EF-hand motifs mediate Ca2+ binding and contribute to Ca2+ modulation of the RYR1 channel (11). In RYR2, the EF-hand motifs are not required for cytosolic Ca2+ modulation of the RYR2 channel, but are required for luminal Ca2+ modulation of the RYR2 channel and for store overload-induced Ca2+ release (12). The luminal loops within the transmembrane domain region of the RYR2 monomers contribute to the pore structure and amino acids Glu4832, Ile4829, Gly4826, and Gln4881 (rabbit RYR2) directly mediate Ca2+ passage through the pore (13-15). The last 15 amino acids of the C-terminal tail are putatively required for tetramer formation (16). A second study proposed that the tetramerization domain was between amino acids 4869 and 5019 in RyR1 (17). Single-particle electron microscopy (EM) of stained and unstained frozen-hydrated RYR2 showed a four-fold symmetric mushroom-shaped architecture, with the four copies of the cytosolic domain forming an umbrella, and a small cylindric transmembrane domain containing the pore [Figure 4; PDB: 5GOA; (18;19). Later studies using high-resolution cryo-EM showed that RYR1 (and RYR2) has an insertion between the S2 and S3 helices (S2S3 domain), a 90 Å long pore helix ending with a C-terminal domain containing a zinc finger and an acidic disordered loop between S1 and S2 (20). The activation domain contains a domain in the shape of a thumb and forefingers, which clamps the zinc finger-containing C-terminal domain. RYRs are principally composed of three α-solenoid repeats. The core solenoid (CSol) is part of the activation domain, and links the pore domain to the shell. The bridging (BSol) and N-terminal solenoids (NSol) are joined by the junctional solenoid (JSol) (21). The RYRs are closed at low levels of cytosolic Ca2+ ([Ca2+] ~100–200 nM). Increased levels of cytosolic Ca2+ ([Ca2+]cyto ~10 μM) stimulate channel opening. RYR2 undergoes conformational changes when opening, including expansion of the clamp domain, rotation of the transmembrane domains relative to the cytoplasmic region, and expansion of the pore to 18 Å (15;22;23). RYR2 is phosphorylated at Ser2808, Ser2814, and Ser2030. Other sites (e.g., Thr2876, Thr2781, Tyr2821, and Ser2822) can also be putatively phosphorylated by protein kinase A (PKA). Ser2808 can be phosphorylated by both PKA and Ca2+/calmodulin-dependent protein kinase II (CaMKII) (24;25). High basal levels of Ser2808 phosphorylation is important for normal excitation–contraction coupling (26-28). CamKII phosphorylates Ser2814, which increases the Ca2+ sensitivity and open probability (Po) of RYR2 (29-31). Ser2030 is phosphorylated by PKA and protein kinase G (but not CaMKII) (32;33). Ser2030 phosphorylation affects RYR2 sensitivity during b-adrenergic stimulation. For more information on the effects of RYR2 phosphorylation, see Table 1 and Table 2 (in the Background section). RYRs interact with several ligands that putatively regulate gating of the channel, including ions (primarily Ca2+ and Mg2+), the voltage-gated Ca2+ channel, and small molecules (e.g., adenine nucleotides and caffeine) (21). RYR2 also serves as a scaffold for several regulatory subunits and enzymes (Table 1). Table 1. RYR2-associated regulatory proteins
RYR2 interacting region
|
Regulatory protein
|
Description
|
RYR2-associated function
|
References
|
Cytoplasmic N-terminus
|
FKBP12.6 (alternatively, calstabin2) and FKBP12 (putatively species specific)
|
Immunophilins and FK-506 binding proteins
|
Stabilizes the closed state of the channel and prevents the pathological leak of Ca2+
|
(34-37)
|
Calmodulin
|
Ca2+-binding protein
|
Inhibits RYR2 at [Ca2+] < 10 μM; assists RYR2 closing after sarcoplasmic reticulum Ca2+ release in EC-coupling
|
(38-41)
|
CaMKII
|
Kinase
|
Phosphorylates Ser2815 (Ser2814 in mouse), which sensitizes the channel to cytosolic Ca2+
|
(10;42;43)
|
PKA
|
Kinase
|
Phosphorylates Ser2809 (Ser2808 in mouse) and Ser2030, which activates the channel by increasing the sensitivity of RyR2 to cytosolic Ca2+ and promoting dissociation from FKBP12.6
|
(26;42;44)
|
3′,5′-cyclic phosphodiesterase 4D (pDE4D)
|
cAMP-specific enzyme
|
Provides negative-feedback mechanism to limit phosphorylation of RyR2-Ser2808
|
(45)
|
mAKAP
|
Scaffold protein
|
Targets PKA and pDE4D to RYR2 |
(46;47)
|
Sorcin
|
Ca2+-binding protein
|
Reduces the Po
of RYR2
|
(48;49)
|
Spinophilin and PR130
|
Spinophilin: PP1 regulatory subunit; PR130: PP2A regulatory subunit
|
Target the protein phosphatases PP1 and PP2A to RyR2
|
(10)
|
PP1 (anchored by spinophilin) and PP2A (anchored by PR130)
|
Phosphatases
|
Regulates channel activity
|
(10;42)
|
C-terminus
|
Calsequestrin
|
Ca2+-binding protein which sequesters Ca2+ in the sarcoplasmic reticulum
|
Regulates RYR2 activity
|
(50)
|
Triadin
|
Integral sarcoplasmic reticulum membrane protein
|
Necessary for proper orientation and activity of the RYR-L-type Ca2+ channel Ca2+ release unit; links calsequestrin to RYR2
|
(51)
|
Junctin
|
Integral sarcoplasmic reticulum membrane protein
|
Stabilizes RYR2 in the myocardium |
(52)
|
Ryr2 is alternatively spliced (removing exons 4 [corresponding to amino acids 92 to 98 in human RYR2] and 75 [corresponding to amino acids 3564 to 3575 in human RYR2]) to generate a mRNA that is predominantly expressed in pancreatic islets, cerebrum, and cerebellum (53). HEK293 cells transfected with the “islet-type” RYR2 expression vector showed increased Ca2+ release after treatment with cyclic ADP-ribose (stimulates intracellular Ca2+ mobilization) compared to cells transfected with a canonical RYR2 expression vector (53). Two additional alternatively spliced variants with 30- and 24-base pair insertions have been identified in humans (54). The two variants were expressed in cardiomyocytes and localized to the sarcoplasmic reticulum, perinuclear Golgi apparatus, and invaginations of the nuclear envelope (nucleoplasmic reticulum). The 24-base pair variant was required for RYR2 targeting to the intranuclear Golgi apparatus. Expression of the 30- and 24-base pair splice variants resulted in reduced amplitude variability of nuclear and cytoplasmic Ca2+ fluxes in nonstimulated cardiomyocytes as well as lower basal levels of apoptosis (54). Expression of the 24-base pair variant suppressed intracellular Ca2+ fluxes following prolonged caffeine exposure that protected cells from apoptosis. The 30-base pair variant did not protect cardiomyocytes from caffeine-evoked apoptosis. The Arruda mutation results in an arginine (R) to glutamine (Q) substitution at position 3,614 (R3614Q); Arg3614 is within an undefined region between the last leucine zipper and the first EF-hand motif.
|
Expression/Localization | RYR2 is expressed in cardiomyocytes, pancreatic islets, and the dentate gyrus of the hippocampus (31;55). RYR2 localizes to the membrane of the sarcoplasmic reticulum.
|
Background |
Ca2+ signaling is essential for development, proliferation, neuronal transmission, learning and memory, muscle contraction, cell motility, cell growth, and cell death as well as regulation of enzyme activity, permeability of ion channels, and activity of ion pumps [reviewed in (56)]. RYR2-associated Ca2+ release is required for cardiac muscle excitation-contraction coupling [(57;58); reviewed in (59)]. In cardiac muscle, depolarization of the plasma membrane activates Ca2+ influx via the L-type Ca2+ channel (Cav1.2; see the record hera for more information about voltage-dependent calcium channels), which subsequently activates RYR2 (Figure 5) (60). Calcium sensors within RYR2 bind calcium and facilitate opening of the channel, resulting in release of calcium from the sarcoplasmic reticulum via the Ca2+-induced Ca2+-release (CICR) mechanism (59;61). The CICR mechanism causes a transitory increase in intracellular Ca2+ that binds to troponin C, enabling actin-myosin binding and signaling contractile myofilaments to generate force, sarcomere shortening, and myocardial contraction. Termination of sarcoplasmic reticulum Ca2+ release promotes relaxation. During relaxation, Ca2+ returns to diastolic Ca2+ levels via the activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a and the sarcolemma Na+/Ca2+ exchanger (NCX) [reviewed in (62)]. RYR2 also functions in cognitive function (63) and insulin secretion (64). Ca2+ signaling regulates insulin secretion from the islets of Langerhans. Insulin secretion largely depends on voltage-activated Ca2+ influx, and RYR2 regulates β cell insulin release and glucose homeostasis (64). Mutations that are linked to aberrant RYR2 function in cardiac myocytes also cause impaired glucose homeostasis, activation of the ER stress response, and fuel-stimulated insulin release (64). Mutations in RYR2 are linked to arrhythmogenic right ventricular dysplasia 2 [ARVD2; OMIM: #600996; (65;66)] and catecholaminergic polymorphic ventricular tachycardia 1 [CPVT1; OMIM: #604772; (67;68)]. ARVD2 is characterized by partial degeneration of the myocardium of the right ventricle, effort-induced polymorphic ventricular tachycardias, and sudden death. CPVT1 is characterized by a reproducible form of polymorphic ventricular tachycardia induced by physical activity, stress, or catecholamine infusion, which can deteriorate into ventricular fibrillation. Patients exhibit recurrent syncope, seizures, or sudden death after physical activity or emotional stress; the heart is morphologically normal. Several mouse Ryr2 mutant mouse strains have been generated and characterized (Table 2). Most mutant mice showed heart rhythm abnormalities due to aberrant channel function, and some mutations resulted in sudden death of the mouse. Table 2. Phenotypes of RYR2 mutant mice
Mutation
|
Mutation note
|
Phenotype (homozygous)
|
References
|
Ryr2-/-
|
Removed the first protein coding sequence of 48 base pairs and part of the first intron |
Embryonic lethality (~E10.5), abnormal cardiomyocyte morphology, abnormal myocardial trabeculae morphology, disorganized myocardium, abnormal epicardium morphology, and embryonic growth retardation
|
(69) & MGI
|
Ryr2flox/ Ryr2flox
A1cfTg(Myh6-cre/Esr1*)1Jmk/0
|
Inducible, cardiac-specific RYR2 knockout
|
Bradycardia, arrhythmia, lethargy sudden death |
(70)
|
RYR2 Ex3-del (exon 3 deletion)
|
Mimics human CPVT1 mutation
|
Embryonic lethal; heterozygous cardiomyocytes showed increased time-to-peak and time-to-50% decay of calcium release evoked by depolarization
|
(71)
|
R176Q
|
ARVD2
|
Reduced right ventricular end-diastolic volume, and the mice showed ventricular tachycardia after caffeine and epinephrine injection
|
(72;73)
|
L433P
|
Mimics human CPVT1 mutation
|
Atrial fibrillation, leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes
|
(74)
|
R420W
|
ARVD2
|
Increased thymus and spleen weights as well as increased lymphocytic density in the spleen; heart morphology was normal
|
(75)
|
S2246L*
|
Mimics human CPVT1 mutation
|
Ventricular tachycardia; cardiomyocytes exhibit reduced threshold of sarcoplasmic reticulum calcium load for channel activation
|
(76)
|
P2328S
|
Mimics human CPVT1 mutation
|
Ventricular tachycardia
|
(77)
|
R2386I*
|
Mimics human CPVT1 mutation
|
Atrial fibrillation and leaky calcium channels in the sarcoplasmic reticulum of atrial myocytes
|
|
R2474S
|
Mimics human CPVT1 mutation
|
Spontaneous generalized tonic-clonic seizures (in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden death
|
(78)
|
V2475F
|
Mimics human CPVT1 mutation
|
Embryonic lethality (~E9); heterozygous mice showed normal cardiac morphology and functional echocardiogram at rest, but irregular heartbeats after beta-adrenergic stimulation
|
(79)
|
S2080A
|
PKA phosphorylation mutant
|
In the absence of induced myocardial infarction, the morphology of homozygous hearts is similar to wild-type; less susceptibility to myocardial infarction-induced heart failure; cardiomyocytes showed slower time constant of decay for calcium transients
|
(26-28)
|
S2814A
|
CaMKII phosphorylation mutant
|
Ventricular tachycardia; increased response of heart to induced stress
|
(73;80)
|
S2814D
|
CaMKII phosphorylation mutant
|
Reduced cardiac muscle contractility, reduced heart rate and ventricular tachycardia after treatment with caffeine and epinephrine, increased response of the heart to induced stress
|
(80)
|
W3587A/L3591AD/F3603A
|
In exon 75, which encodes the CaM-binding site of RyR2 |
Postnatal lethality (P9), enlarged hearts, cardiac fibrosis, reduced ventricle muscle contractility, reduced heart rates, reduced body weights, thin interventricular septum
|
(81)
|
L3591D
|
Eliminates CaM and S100A1 inhibition
|
Increased heart weight, thick interventricular septum, cardiac hypertrophy
|
(82)
|
R4496C
|
Mimics human CPVT1 mutation
|
Increase in RYR2 channel activity, ventricular fibrillation, ventricular tachycardia, and enhanced RYR2 sensitivity to Ca2+ and caffeine
|
(83;84)
|
A4860G
|
Mimics human CPVT1 mutation
|
Prenatal lethality; heterozygotes showed reduced heart rate and ventricular fibrillation
|
(85)
|
E4872Q
|
E4872 is an element of the RYR2 luminal Ca2+ sensing mechanism
|
Embryonic lethality (~E10.5); heterozygous mice are resistant to store overload-induced Ca2+ waves and completely protected against Ca2+-triggered ventricular tachycardia
|
(86)
|
* Studied in heterozygous mice only
|
Putative Mechanism | The phenotype of the Arruda mice indicates loss of RYR2-associated function.
|
Primers |
PCR Primer
Arruda_pcr_F: GTCATAACCAGTAAATGTGGCAAC
Arruda_pcr_R: ACCCAAAGTCAGTATGTGATCTGAG
Sequencing Primer
Arruda_seq_F: GGCAACAGTGAGAATTAAAGTTTTC
Arruda_seq_R: GTCAGTATGTGATCTGAGAAAACTGC
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 406 nucleotides is amplified (chromosome 13, - strand):
1 acccaaagtc agtatgtgat ctgagaaaac tgcttttatt ggatgcaagg agttgtctgt 61 gaagagagga atcaataata ggaagtttat tttttatttt atattttagt gcacagatca 121 tctggtaata agcactattg aattcttgtt catatattta aaatcccttt gtttgacatt 181 gcatttatct tttaggcatc gggcggtcaa tctttttctt cagggatatg aaaagtcttg 241 gattgaaaca gaagaacatt actttgagga taaattgatt gaagatttag cggtaagctt 301 tttaatgaga ttataaaatg aaagaagatg gaaagaaaat cattacactg catgttggtc 361 ttagaaaact ttaattctca ctgttgccac atttactggt tatgac
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
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Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Samantha Teixeira and Bruce Beutler |