Submissions for variant NM_000540.3(RYR1):c.11132C>T (p.Thr3711Met)

dbSNP: rs375915752

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001450002	SCV001653552	uncertain significance	Malignant hyperthermia, susceptibility to, 1	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 threonine with methionine at codon 3711 of the RYR1 protein, p.(Thr3711Met). 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 an individual who had a personal or family history of a malignant hyperthermia reaction and 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_Supporting (PMID:30236257). This family presented with four informative meiosis, (PMID:30236257, The UK (Leeds) MH Unit), PP1. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.637 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001872007	SCV002131809	pathogenic	RYR1-related disorder	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3711 of the RYR1 protein (p.Thr3711Met). This variant is present in population databases (rs375915752, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions and/or malignant hyperthermia (PMID: 30236257, 32054689). ClinVar contains an entry for this variant (Variation ID: 1120229). 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. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV001450002	SCV004812879	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001450002	SCV004820993	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-08-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005057412	SCV005726371	uncertain significance	not specified	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.11132C>T (p.Thr3711Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248650 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11132C>T has been reported in the literature in at least two individuals affected with Malignant Hyperthermia Susceptibility confirmed by in vitro contracture testing, however at least one of these individuals harbored other variants of unknown significance in RYR1 (e.g. Miller_2018, Chang_2019, Gardner_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility or other RYR1-related disorders. 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: 30916033, 32054689, 35849058, 30236257). ClinVar contains an entry for this variant (Variation ID: 1120229). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV001872007	SCV005362186	uncertain significance	RYR1-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The RYR1 c.11132C>T variant is predicted to result in the amino acid substitution p.Thr3711Met. This variant was reported in multiple individuals from two families with malignant hyperthermia, including at least one individual with a positive in vitro contracture test result (Gardner et al. 2020. PubMed ID: 32054689; Miller et al. 2018. PubMed ID: 30236257). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is classified as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/1120229/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.