Submissions for variant NM_000540.3(RYR1):c.8290G>A (p.Glu2764Lys)

gnomAD frequency: 0.00001  dbSNP: rs193922829

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001802880	SCV002047630	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 glutamic acid with lysine at codon 2764 of the RYR1 protein, p.(Glu2764Lys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.000109, a frequency consistent with pathogenicity for MHS. To our knowledge, this variant has not been reported in any individuals with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT). 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 0.842 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455061	SCV000540252	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 MH proband, structural analysis suggests variant falls on same face of a phosphorylation as other predicted pathogenic variants.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735351	SCV000854505	uncertain significance	Ankyloglossia; Coarctation of aorta; Atrial septal defect; Heart block; Clinodactyly of the 5th finger; Generalized hypotonia; Delayed gross motor development; Bronchomalacia; Sagittal craniosynostosis; Bilateral single transverse palmar creases; Bicoronal synostosis; Ventricular septal defect		criteria provided, single submitter	clinical testing
GeneDx	RCV000119743	SCV004025572	likely pathogenic	not provided	2023-08-07	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in an individual with repeated episodes of generalized normokalemic paralysis (Luo et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22705209, 35677449, 31068157, 12668474, 16835904)
PreventionGenetics, part of Exact Sciences	RCV003415903	SCV004116853	uncertain significance	RYR1-related condition	2023-10-10	criteria provided, single submitter	clinical testing	The RYR1 c.8290G>A variant is predicted to result in the amino acid substitution p.Glu2764Lys. This variant was previously reported in a patient with malignant hyperthermia and in another individual with primary periodic paralysis; however, pathogenicity was not established with segregation or functional analysis (Galli et al. 2006. PubMed ID: 16835904; Luo et al. 2019. PubMed ID: 31068157). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38995701-G-A). This variant is interpreted as uncertain in ClinVar by the ClinGen Malignant Hyperthermia Susceptibility Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133221/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Muscular Dystrophy (RYR1)	RCV000119743	SCV000154650	not provided	not provided		no assertion provided	not provided