Submissions for variant NM_000540.3(RYR1):c.10204T>G (p.Cys3402Gly)

gnomAD frequency: 0.00005  dbSNP: rs367543058

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147397	SCV000194776	pathogenic	not provided	2013-12-02	criteria provided, single submitter	clinical testing
Center for Genetic Medicine Research, Children's National Medical Center	RCV000233916	SCV000265781	likely pathogenic	Central core myopathy	2015-12-01	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000147397	SCV000335753	uncertain significance	not provided	2015-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000147397	SCV000521246	likely pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Identified in individuals who did not harbor a second RYR1 variant, who had features of congenital onset RYR1-related disease (PMID: 27854218); Not observed at significant frequency in large population cohorts (gnomAD); 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: 23069638, 20583297, 27854218)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000401146	SCV000540253	uncertain significance	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in association with myopathy (congenital fiber type disproportion), in only 1 proband.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529599	SCV000659742	pathogenic	RYR1-related disorder	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 3402 of the RYR1 protein (p.Cys3402Gly). This variant is present in population databases (rs367543058, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy, and congenital fiber type disproportion (CFTD) (PMID: 20583297, 27854218; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42098). 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 RYR1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000147397	SCV001246301	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR1: PM2, PM3, PP3, PP4
Revvity Omics, Revvity	RCV000147397	SCV002019104	likely pathogenic	not provided	2020-09-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996181	SCV004820975	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 3402 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 42098; PMID: 20583297, 27854218). This variant has been identified in 7/262002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
GeneReviews	RCV000034925	SCV000058532	not provided	Congenital myopathy with fiber type disproportion		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV000529599	SCV004118305	likely pathogenic	RYR1-related disorder	2023-11-29	no assertion criteria provided	clinical testing	The RYR1 c.10204T>G variant is predicted to result in the amino acid substitution p.Cys3402Gly. This variant has been reported in the compound heterozygous state in an individual with congenital fiber type disproportion (Clarke et al. 2010. PubMed ID: 20583297). It has also been reported in the heterozygous state in an individual with congenital fiber type disproportion that did not have a second pathogenic variant (Punetha et al. 2016. PubMed ID: 27854218). This variant is reported in 0.0059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar of uncertain, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/42098/). Based on the available evidence, we consider the RYR1 c.10204T>G (p.Cys3402Gly) variant to be likely pathogenic.