Submissions for variant NM_000540.3(RYR1):c.2920G>A (p.Val974Met)

gnomAD frequency: 0.00004  dbSNP: rs748676912

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366304	SCV001562604	uncertain significance	RYR1-related disorder	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 974 of the RYR1 protein (p.Val974Met). This variant is present in population databases (rs748676912, gnomAD 0.005%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 19191333). ClinVar contains an entry for this variant (Variation ID: 1057344). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001773727	SCV001994601	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in patients with malignant hyperthermia in published literature (Zullo et al., 2009; Brandom et al., 2013), but additional clinical information was not included; This variant is associated with the following publications: (PMID: 19191333, 23558838)
Revvity Omics, Revvity	RCV001773727	SCV003814447	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004006800	SCV004820790	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 974 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with malignant hyperthermia and in one individual who was not found to be susceptible to malignant hyperthermia (PMID: 23558838, 19191333). This variant has been identified in 9/278206 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004006800	SCV005398058	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related myopathy. Central core disease and minicore myopathy are associated with loss of function, while a gain of function mechanism has been described in the context of malignant hyperthermia susceptibility (MHS) (PMID: 27855725). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant inheritance is associated with central core disease (MIM#117000) or MHS (MIM#145600). Other phenotypes including minicore myopathy (MIM#255320) are associated with autosomal recessive inheritance (PMID: 23919265). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RYR domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. This variant has been described twice as a polymorphism, and observed in both an MHS and a control cohort. Analysis of contracture by caffeine and halothane was inconclusive (PMID: 23558838, PMID: 19191333). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign