Submissions for variant NM_000540.3(RYR1):c.12532G>A (p.Gly4178Ser)

dbSNP: rs1057518885

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV003221969	SCV003915968	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-10	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 serine at codon 4178 of the RYR1 protein, p.(Gly4178Ser). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode 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: 24433488). 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 >0.85 (0.979) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PP3_Moderate.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002051703	SCV000492824	likely pathogenic	Malignant hyperthermia of anesthesia	2015-07-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057328	SCV001221815	pathogenic	RYR1-related disorder	2020-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 4178 of the RYR1 protein (p.Gly4178Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. For these reasons, this variant has been classified as Pathogenic. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that this may be a clinically significant region of the protein. 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. This variant has been observed in individual(s) with malignant hyperthermia (PMID: 24433488). ClinVar contains an entry for this variant (Variation ID: 374083). This variant is not present in population databases (ExAC no frequency).