Submissions for variant NM_000540.3(RYR1):c.13913G>A (p.Gly4638Asp)

dbSNP: rs118192135

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001450011	SCV001653561	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 glycine with aspartic acid at codon 4638 of the RYR1 protein, p.(Gly4638Asp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in one individual with a personal or family history of a malignant hyperthermia reaction. This individual did not have an in vitro contracture test (IVCT) or a caffeine halothane contracture test (CHCT) result, PS4 not implemented (PMID: 16732084). 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_Supporting (PMID: 21118704). A REVEL score >0.85 (0.917) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate.
PreventionGenetics, part of Exact Sciences	RCV000119490	SCV000852376	pathogenic	not provided	2013-11-22	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198930	SCV001369925	likely pathogenic	Congenital myopathy with fiber type disproportion	2019-01-09	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PS1,PM6.
Revvity Omics, Revvity	RCV000119490	SCV003812063	likely pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003591652	SCV004311827	pathogenic	RYR1-related disorder	2022-12-31	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 4638 of the RYR1 protein (p.Gly4638Asp). This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR1-related conditions (PMID: 12565913, 14985404, 28357410). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly4638Ser amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16621918, 23394784). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 65941).
GeneReviews	RCV000056188	SCV000087277	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119490	SCV000154397	not provided	not provided		no assertion provided	not provided