Phenotypic Mutation 'Arruda2' (pdf version)
Allele | Arruda2 |
Mutation Type |
missense
|
Chromosome | 13 |
Coordinate | 11,894,382 bp (GRCm39) |
Base Change | G ⇒ 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 |
Serine changed to Arginine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000021750]
[ENSMUSP00000127991]
[ENSMUSP00000152051]
|
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: S185R
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 |
probably damaging
PolyPhen 2
Score 0.997 (Sensitivity: 0.41; Specificity: 0.98)
(Using ENSMUST00000021750)
|
SMART Domains |
Protein: ENSMUSP00000127991 Gene: ENSMUSG00000021313 AA Change: S185R
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 0.998 (Sensitivity: 0.27; Specificity: 0.99)
(Using ENSMUST00000170156)
|
Predicted Effect |
probably damaging
PolyPhen 2
Score 0.996 (Sensitivity: 0.55; Specificity: 0.98)
(Using ENSMUST00000220597)
|
Meta Mutation Damage Score |
0.2762 |
Is this an essential gene? |
Essential (E-score: 1.000) |
Phenotypic Category |
Unknown |
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 |
Arruda
|
UTSW |
13 |
11658781 |
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 |
Unknown |
Local Stock | |
Repository | |
Last Updated |
2019-10-29 9:58 AM
by Anne Murray
|
Record Created |
2018-07-13 7:12 PM
by Bruce Beutler
|
Record Posted |
2018-10-24 |
Phenotypic Description |
The Arruda2 phenotype was identified among G3 mice of the pedigree R6294, some of which showed reduced heart rates compared to wild-type littermates (Figure 1).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 72 mutations. The heart rate phenotype was linked by continuous variable mapping to a mutation in Ryr2: a C to A transversion at base pair 11,879,496 (v38) on chromosome 13, or base pair 227,450 in the GenBank genomic region NC_000079. Linkage was found with an additive model of inheritance, wherein three variant homozygotes and 26 heterozygous mice departed phenotypically from 23 homozygous reference mice with a P value of 2.127 x 10-7 (Figure 2). The mutation corresponds to residue 1,054 in the mRNA sequence NM_023868 within exon 8 of 105 total exons.
1037 GATCTCATCTTGGTCAGCGTGTCCTCAGAAAGG
180 -D--L--I--L--V--S--V--S--S--E--R-
|
The mutated nucleotide is indicated in red. The mutation results in a serine to arginine substitution at position 185 (S185R) in the RYR2 protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 0.997).
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
Ryr2 encodes cardiac ryanodine receptor 2 (RYR2). RYR2 has a large (amino acids 1 to 4,231) cytoplasmic N-terminal tail, six transmembrane domains, and a short C-terminal tail (amino acids 4,870 to 4,966). The luminal loops 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 (1-3). RYR2 has an N-terminal domain, three SPRY domains, four armadillo repeat-containing domains (termed the Handle domain), five MIR domains, two RyR domains (alternatively P1 and P2 domains), three leucine zippers, and two putative EF-hand motifs (4-8). The three-dimensional structure of the N-terminal domain 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) (7;9). The Arruda2 mutation results in a serine to arginine substitution at position 185 (S185R); Ser185 is within the first MIR domain (in subdomain A). 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 (10) and subdomain A is involved in channel termination. Please see the record Arruda for more information about Ryr2.
|
Putative Mechanism | RYR2-associated Ca2+ release is required for cardiac muscle excitation-contraction coupling [(11;12); reviewed in (13)]. 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 (14). 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 (13;15). 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 (16)]. Mutations in RYR2 are linked to arrhythmogenic right ventricular dysplasia 2 [ARVD2; OMIM: #600996; (17;18)] and catecholaminergic polymorphic ventricular tachycardia 1 [CPVT1; OMIM: #604772; (19;20)]. 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. Most homozygous mutants were embryonic lethal. Heterozygous mutant mice (or homozygotes that were not embryonic lethal) showed heart rhythm abnormalities due to aberrant channel function, and some mutations resulted in sudden death of the mouse (21-41). The phenotype of the Arruda2 mice mimics that of other Ryr2 mutant mice, indicating loss of RYR2-associated function.
|
Primers |
PCR Primer
Arruda2_pcr_F: GGAAGCCTGCTCAAACAGAC
Arruda2_pcr_R: TTCTGAACGTCCCTTGAGTGG
Sequencing Primer
Arruda2_seq_F: TGCTCAAACAGACCCAGGGAG
Arruda2_seq_R: GTCCCTTGAGTGGCGTCATC
|
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 416 nucleotides is amplified (chromosome 13, - strand):
1 ttctgaacgt cccttgagtg gcgtcatctg gagagggaat ggatcttcaa ttaactgggt 61 tttctccatg ttttaattct ataattcgca ggggaggctt gctggtggac catacatcct 121 gcctctaagc agagatcaga aggagaaaaa gtgcgtgttg gagatgatct catcttggtc 181 agcgtgtcct cagaaaggta cttggtaagt gtggggacat ggcttcatgc ttgatgctct 241 gctgagagcg ggagatgaag tgatgcttgg taggaaatgt gcttatgagc aagcaaagct 301 agggagacaa ttcataaagg cttgtgcctc tagctataaa taactcctga gaagagaggg 361 agatgtctgt ggccttacgg ggagatggct ccctgggtct gtttgagcag gcttcc
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
6. Yuchi, Z., Yuen, S. M., Lau, K., Underhill, A. Q., Cornea, R. L., Fessenden, J. D., and Van Petegem, F. (2015) Crystal Structures of Ryanodine Receptor SPRY1 and Tandem-Repeat Domains Reveal a Critical FKBP12 Binding Determinant. Nat Commun. 6, 7947.
7. Amador, F. J., Liu, S., Ishiyama, N., Plevin, M. J., Wilson, A., MacLennan, D. H., and Ikura, M. (2009) Crystal Structure of Type I Ryanodine Receptor Amino-Terminal Beta-Trefoil Domain Reveals a Disease-Associated Mutation "Hot Spot" Loop. Proc Natl Acad Sci U S A. 106, 11040-11044.
8. Liu, Y., Sun, B., Xiao, Z., Wang, R., Guo, W., Zhang, J. Z., Mi, T., Wang, Y., Jones, P. P., Van Petegem, F., and Chen, S. R. (2015) Roles of the NH2-Terminal Domains of Cardiac Ryanodine Receptor in Ca2+ Release Activation and Termination. J Biol Chem. 290, 7736-7746.
9. Borko, L., Bauerova-Hlinkova, V., Hostinova, E., Gasperik, J., Beck, K., Lai, F. A., Zahradnikova, A., and Sevcik, J. (2014) Structural Insights into the Human RyR2 N-Terminal Region Involved in Cardiac Arrhythmias. Acta Crystallogr D Biol Crystallogr. 70, 2897-2912.
10. Serysheva, I. I., Ludtke, S. J., Baker, M. L., Cong, Y., Topf, M., Eramian, D., Sali, A., Hamilton, S. L., and Chiu, W. (2008) Subnanometer-Resolution Electron Cryomicroscopy-Based Domain Models for the Cytoplasmic Region of Skeletal Muscle RyR Channel. Proc Natl Acad Sci U S A. 105, 9610-9615.
11. Otsu, K., Willard, H. F., Khanna, V. K., Zorzato, F., Green, N. M., and MacLennan, D. H. (1990) Molecular Cloning of cDNA Encoding the Ca2+ Release Channel (Ryanodine Receptor) of Rabbit Cardiac Muscle Sarcoplasmic Reticulum. J Biol Chem. 265, 13472-13483.
12. Nakai, J., Imagawa, T., Hakamat, Y., Shigekawa, M., Takeshima, H., and Numa, S. (1990) Primary Structure and Functional Expression from cDNA of the Cardiac Ryanodine receptor/calcium Release Channel. FEBS Lett. 271, 169-177.
17. Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., and Rampazzo, A. (2001) Identification of Mutations in the Cardiac Ryanodine Receptor Gene in Families Affected with Arrhythmogenic Right Ventricular Cardiomyopathy Type 2 (ARVD2). Hum Mol Genet. 10, 189-194.
18. Rampazzo, A., Nava, A., Erne, P., Eberhard, M., Vian, E., Slomp, P., Tiso, N., Thiene, G., and Danieli, G. A. (1995) A New Locus for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVD2) Maps to Chromosome 1q42-q43. Hum Mol Genet. 4, 2151-2154.
19. Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., and Danieli, G. A. (2001) Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation. 103, 196-200.
20. Laitinen, P. J., Brown, K. M., Piippo, K., Swan, H., Devaney, J. M., Brahmbhatt, B., Donarum, E. A., Marino, M., Tiso, N., Viitasalo, M., Toivonen, L., Stephan, D. A., and Kontula, K. (2001) Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia. Circulation. 103, 485-490.
21. Takeshima, H., Komazaki, S., Hirose, K., Nishi, M., Noda, T., and Iino, M. (1998) Embryonic Lethality and Abnormal Cardiac Myocytes in Mice Lacking Ryanodine Receptor Type 2. EMBO J. 17, 3309-3316.
22. Bround, M. J., Asghari, P., Wambolt, R. B., Bohunek, L., Smits, C., Philit, M., Kieffer, T. J., Lakatta, E. G., Boheler, K. R., Moore, E. D., Allard, M. F., and Johnson, J. D. (2012) Cardiac Ryanodine Receptors Control Heart Rate and Rhythmicity in Adult Mice. Cardiovasc Res. 96, 372-380.
23. Liu, Y., Wang, R., Sun, B., Mi, T., Zhang, J., Mu, Y., Chen, J., Bround, M. J., Johnson, J. D., Gillis, A. M., and Chen, S. R. (2014) Generation and Characterization of a Mouse Model Harboring the Exon-3 Deletion in the Cardiac Ryanodine Receptor. PLoS One. 9, e95615.
24. Kannankeril, P. J., Mitchell, B. M., Goonasekera, S. A., Chelu, M. G., Zhang, W., Sood, S., Kearney, D. L., Danila, C. I., De Biasi, M., Wehrens, X. H., Pautler, R. G., Roden, D. M., Taffet, G. E., Dirksen, R. T., Anderson, M. E., and Hamilton, S. L. (2006) Mice with the R176Q Cardiac Ryanodine Receptor Mutation Exhibit Catecholamine-Induced Ventricular Tachycardia and Cardiomyopathy. Proc Natl Acad Sci U S A. 103, 12179-12184.
25. Chelu, M. G., Sarma, S., Sood, S., Wang, S., van Oort, R. J., Skapura, D. G., Li, N., Santonastasi, M., Muller, F. U., Schmitz, W., Schotten, U., Anderson, M. E., Valderrabano, M., Dobrev, D., and Wehrens, X. H. (2009) Calmodulin Kinase II-Mediated Sarcoplasmic Reticulum Ca2+ Leak Promotes Atrial Fibrillation in Mice. J Clin Invest. 119, 1940-1951.
26. Shan, J., Xie, W., Betzenhauser, M., Reiken, S., Chen, B. X., Wronska, A., and Marks, A. R. (2012) Calcium Leak through Ryanodine Receptors Leads to Atrial Fibrillation in 3 Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia. Circ Res. 111, 708-717.
27. Nishio, H., Okudaira, N., Matsushita, K., Yoshimoto, T., Sato, T., and Suzuki, K. (2014) Hypertrophy of Lymphoid Organs is a Possible Phenotypic Characteristic of R420W Mutation of the Cardiac Ryanodine Receptor Gene: A Study using a Knock-in Mouse Model. Leg Med (Tokyo). 16, 326-332.
28. Suetomi, T., Yano, M., Uchinoumi, H., Fukuda, M., Hino, A., Ono, M., Xu, X., Tateishi, H., Okuda, S., Doi, M., Kobayashi, S., Ikeda, Y., Yamamoto, T., Ikemoto, N., and Matsuzaki, M. (2011) Mutation-Linked Defective Interdomain Interactions within Ryanodine Receptor Cause Aberrant Ca(2)(+)Release Leading to Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation. 124, 682-694.
29. Goddard, C. A., Ghais, N. S., Zhang, Y., Williams, A. J., Colledge, W. H., Grace, A. A., and Huang, C. L. (2008) Physiological Consequences of the P2328S Mutation in the Ryanodine Receptor (RyR2) Gene in Genetically Modified Murine Hearts. Acta Physiol (Oxf). 194, 123-140.
30. Lehnart, S. E., Mongillo, M., Bellinger, A., Lindegger, N., Chen, B. X., Hsueh, W., Reiken, S., Wronska, A., Drew, L. J., Ward, C. W., Lederer, W. J., Kass, R. S., Morley, G., and Marks, A. R. (2008) Leaky Ca2+ Release channel/ryanodine Receptor 2 Causes Seizures and Sudden Cardiac Death in Mice. J Clin Invest. 118, 2230-2245.
31. Loaiza, R., Benkusky, N. A., Powers, P. P., Hacker, T., Noujaim, S., Ackerman, M. J., Jalife, J., and Valdivia, H. H. (2013) Heterogeneity of Ryanodine Receptor Dysfunction in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia. Circ Res. 112, 298-308.
32. Wehrens, X. H., Lehnart, S. E., Reiken, S., Vest, J. A., Wronska, A., and Marks, A. R. (2006) Ryanodine receptor/calcium Release Channel PKA Phosphorylation: A Critical Mediator of Heart Failure Progression. Proc Natl Acad Sci U S A. 103, 511-518.
33. Benkusky, N. A., Weber, C. S., Scherman, J. A., Farrell, E. F., Hacker, T. A., John, M. C., Powers, P. A., and Valdivia, H. H. (2007) Intact Beta-Adrenergic Response and Unmodified Progression Toward Heart Failure in Mice with Genetic Ablation of a Major Protein Kinase A Phosphorylation Site in the Cardiac Ryanodine Receptor. Circ Res. 101, 819-829.
34. Shan, J., Kushnir, A., Betzenhauser, M. J., Reiken, S., Li, J., Lehnart, S. E., Lindegger, N., Mongillo, M., Mohler, P. J., and Marks, A. R. (2010) Phosphorylation of the Ryanodine Receptor Mediates the Cardiac Fight Or Flight Response in Mice. J Clin Invest. 120, 4388-4398.
35. van Oort, R. J., McCauley, M. D., Dixit, S. S., Pereira, L., Yang, Y., Respress, J. L., Wang, Q., De Almeida, A. C., Skapura, D. G., Anderson, M. E., Bers, D. M., and Wehrens, X. H. (2010) Ryanodine Receptor Phosphorylation by calcium/calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice with Heart Failure. Circulation. 122, 2669-2679.
36. Yamaguchi, N., Takahashi, N., Xu, L., Smithies, O., and Meissner, G. (2007) Early Cardiac Hypertrophy in Mice with Impaired Calmodulin Regulation of Cardiac Muscle Ca Release Channel. J Clin Invest. 117, 1344-1353.
37. Yamaguchi, N., Chakraborty, A., Huang, T. Q., Xu, L., Gomez, A. C., Pasek, D. A., and Meissner, G. (2013) Cardiac Hypertrophy Associated with Impaired Regulation of Cardiac Ryanodine Receptor by Calmodulin and S100A1. Am J Physiol Heart Circ Physiol. 305, H86-94.
39. Cerrone, M., Colombi, B., Santoro, M., di Barletta, M. R., Scelsi, M., Villani, L., Napolitano, C., and Priori, S. G. (2005) Bidirectional Ventricular Tachycardia and Fibrillation Elicited in a Knock-in Mouse Model Carrier of a Mutation in the Cardiac Ryanodine Receptor. Circ Res. 96, e77-82.
40. Zhao, Y. T., Valdivia, C. R., Gurrola, G. B., Powers, P. P., Willis, B. C., Moss, R. L., Jalife, J., and Valdivia, H. H. (2015) Arrhythmogenesis in a Catecholaminergic Polymorphic Ventricular Tachycardia Mutation that Depresses Ryanodine Receptor Function. Proc Natl Acad Sci U S A. 112, E1669-77.
41. Chen, W., Wang, R., Chen, B., Zhong, X., Kong, H., Bai, Y., Zhou, Q., Xie, C., Zhang, J., Guo, A., Tian, X., Jones, P. P., O'Mara, M. L., Liu, Y., Mi, T., Zhang, L., Bolstad, J., Semeniuk, L., Cheng, H., Zhang, J., Chen, J., Tieleman, D. P., Gillis, A. M., Duff, H. J., Fill, M., Song, L. S., and Chen, S. R. (2014) The Ryanodine Receptor Store-Sensing Gate Controls Ca2+ Waves and Ca2+-Triggered Arrhythmias. Nat Med. 20, 184-192.
|
Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Roberto Pontes, Samantha Teixeira, and Bruce Beutler |