1-237808913-G-A

Position:

chr1-237808913-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The ENST00000366574.7(RYR2):c.14311G>A(p.Val4771Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4771F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

RYR2
ENST00000366574.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.96

Variant links:

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) 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]

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000366574.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-237808913-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2125455.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 1-237808913-G-A is Pathogenic according to our data. Variant chr1-237808913-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237808913-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.14311G>A	p.Val4771Ile	missense_variant	100/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.14311G>A	p.Val4771Ile	missense_variant	100/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 19926015). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with CPVT and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 16272262, 19926015, 21292648, 29453246, 26114861, 33606749). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4771 of the RYR2 protein (p.Val4771Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (PMID: 12093772, 19926015, 21292648, 23595086, 26114861). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 26, 2023

Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12093772, 21292648, 21616285, 19398665, 24136861, 29434162, 22383456, 24025405, 15913575, 23022705, 16272262, 25554238, 25651173, 19926015, 26114861, 23595086, 30170228, 28202948, 28237968, 31231889, 31112425) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The p.V4771I pathogenic mutation (also known as c.14311G>A), located in coding exon 100 of the RYR2 gene, results from a G to A substitution at nucleotide position 14311. The valine at codon 4771 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in individuals with known or suspected catecholaminergic polymorphic ventricular tachycardia, and has been reported as occurring de novo in two cases (Priori SG et al. Circulation. 2002;106(1):69-74; Hayashi M et al. Circulation. 2009;119(18):2426-34; Pott C et al. Europace. 2011;13(6):897-901; Van der Werf C et al. J Am Coll Cardiol. 2011;57(22):2244-54; Jabbari J et al. Circ Cardiovasc Genet. 2013;6(5):481-9; Illikova V et al. J Electrocardiol. 2015;48:150-6; Ohno S et al. PLoS ONE. 2015;10(6):e0131517; McLeod KA et al. Cardiol Young. 2017;27(7):1271-1279; Kapplinger JD et al. Circ Genom Precis Med. 2018;11(2):e001424). The variant was reported to co-segregate with disease features in at least two families (Postma AV et al. J Med Genet. 2005; 42(11):863-70; Kawamura M et al. Circ J. 2013; 77(7):1705-13). Additionally, this variant has been reported as occurring in the channel region, considered to be a mutation "hot spot" (Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54(22):2065-74). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.87

N;.

REVEL

Pathogenic

0.77

Sift

Benign

0.13

T;.

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.82

Gain of helix (P = 0.0696);.;

MVP

0.89

MPC

1.5

ClinPred

0.97

GERP RS

4.9

Varity_R

0.28

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over