Submissions for variant NM_000540.3(RYR1):c.946C>T (p.Arg316Cys)

gnomAD frequency: 0.00001  dbSNP: rs752652072

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580400	SCV001810085	uncertain significance	Malignant hyperthermia of anesthesia	2023-04-06	reviewed by expert panel	curation	This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with cysteine at codon 316 of the RYR1 protein, p.(Arg316Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000349, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not met (PMID:31304636). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.793 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.
Illumina Laboratory Services, Illumina	RCV001123355	SCV001282190	uncertain significance	Central core myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001124443	SCV001283405	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001124444	SCV001283406	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001759889	SCV001987369	uncertain significance	not provided	2021-09-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with malignant hyperthermia (Kiatchai et al., 2019); This variant is associated with the following publications: (PMID: 31304636)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856627	SCV002125595	uncertain significance	RYR1-related disorder	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 316 of the RYR1 protein (p.Arg316Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs752652072, ExAC 0.006%). This variant has been observed in individual(s) with malignant hyperthemia (PMID: 31304636). ClinVar contains an entry for this variant (Variation ID: 889434). 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. This variant disrupts the p.Arg316 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 16917943), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002491384	SCV002792956	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-08-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001124443	SCV004815065	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 316 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in one individual affected by a malignant hyperthermia episode (PMID: 31304636). This variant has been identified in 5/251194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.