Submissions for variant NM_000540.3(RYR1):c.7291G>A (p.Asp2431Asn)

gnomAD frequency: 0.00003  dbSNP: rs193922810

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148824	SCV002047607	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-07	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 aspartic acid with asparagine at codon 2431 of the RYR1 protein, p.(Asp2431Asn). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:11575529, PMID:30236257). 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 >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854585	SCV002315833	likely pathogenic	RYR1-related disorder	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2431 of the RYR1 protein (p.Asp2431Asn). This variant is present in population databases (rs193922810, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 11575529). ClinVar contains an entry for this variant (Variation ID: 133194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. This variant disrupts the p.Asp2431 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16917943, 19648156, 30236257; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000119696	SCV003812052	likely pathogenic	not provided	2022-07-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000148824	SCV004358125	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 2431 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 individuals and families affected with malignant hyperthermia susceptibility (PMID: 11575529, 12411786, 15448513, 30236257). This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000148824	SCV004829333	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 2431 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 individuals and families affected with malignant hyperthermia susceptibility (PMID: 11575529, 12411786, 15448513, 30236257). This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525874	SCV005039968	likely pathogenic	Malignant hyperthermia of anesthesia	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.7291G>A (p.Asp2431Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251290 control chromosomes (gnomAD). c.7291G>A has been reported in the literature in heterozygous state in individuals who had a personal and/or family history of malignant hyperthermia, and had a positive caffeine halothane contracture test (CHCT) result (Sambuughin_2001, Sei_2002, Sei_2004). Inaddition, the variant was also reported in an asymptomatic individual with elevated creatine kinase (CK), who also had mild myopathic signs on muscle biopsy (Rubegni_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11575529, 12411786, 15448513, 31517061). ClinVar contains an entry for this variant (Variation ID: 133194). A different missense variant affecting the same amino acid (D2431Y) has been reported in patient(s) affected with malignant hyperthermia (HGMD) and been classified a likely pathogenic in ClinVar by several submitters. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005025190	SCV005647468	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-04-18	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (RYR1)	RCV000119696	SCV000154603	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148824	SCV000190563	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV001854585	SCV000852762	likely pathogenic	RYR1-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The RYR1 c.7291G>A variant is predicted to result in the amino acid substitution p.Asp2431Asn. This variant has been reported in multiple individuals with malignant hyperthermia (Table 2, Sambuughin et al. 2001. PubMed ID: 11575529; Table S1, Robinson et al. 2006. PubMed ID: 16917943; Table 2, Rubegni et al. 2019. PubMed ID: 31517061). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant has been classified as likely pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133194/). An alternate nucleotide change affecting the same amino acid (p.Asp2431Asn) has been reported in multiple families with RYR1-associated disease (Table 3, Miller et al. 2018. PubMed ID: 30236257). This variant is interpreted as likely pathogenic for autosomal dominant RYR1-related disorders and uncertain for autosomal recessive RYR1-related disorders.