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

dbSNP: rs375915752

Total submissions: 4

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	2023-12-01	criteria provided, single submitter	clinical testing