rs794728777

Positions:

• chr1-237778726-G-A
• chr1-237778726-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):​c.11836G>A​(p.Gly3946Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G3946R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237778727-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 644207.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, 0.993
• PP5: Variant 1-237778726-G-A is Pathogenic according to our data. Variant chr1-237778726-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237778726-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11836G>A	p.Gly3946Ser	missense_variant	88/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11836G>A	p.Gly3946Ser	missense_variant	88/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*2928G>A		non_coding_transcript_exon_variant	87/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*2928G>A		3_prime_UTR_variant	87/104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Reported in multiple unrelated individuals with CPVT (Priori et al., 2002; Mok et al., 2006; Wilde et al., 2008; Hayashi et al., 2009; van der Werf et al., 2011; Kawamura et al., 2013; Yu et al., 2016); Not observed in large population cohorts (gnomAD); 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); Functional studies in cultured cells suggest that this variant alters the cytosolic Ca2+ activation of the RYR2 channel, which the authors propose leads to cardiac dysfunction (Xiao et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 12093772, 23595086, 19398665, 27256466, 15544013, 24025405, 21616285, 18463378, 17199967, 19926015, 28449774, 28404607, 29434162, 31337358, 27733687, 34127479, 26114861, 33606749, 34760626) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 23, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3946 of the RYR2 protein (p.Gly3946Ser). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 201315). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 12093772, 21616285, 23595086, 26114861). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.95		Gain of MoRF binding (P = 0.212);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs794728777; hg19: chr1-237942026;