Submissions for variant NM_000540.3(RYR1):c.3494G>A (p.Gly1165Asp)

dbSNP: rs559581937

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147421	SCV000194824	uncertain significance	not provided	2014-01-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237337	SCV001410094	pathogenic	RYR1-related disorder	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1165 of the RYR1 protein (p.Gly1165Asp). This variant is present in population databases (rs559581937, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of autosomal recessive RYR1-related myopathy (PMID: 21911697, 35693006; Invitae). ClinVar contains an entry for this variant (Variation ID: 159843). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000147421	SCV001880061	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000147421	SCV003814459	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000147421	SCV003842465	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Identified with a second RYR1 variant in a patient with congenital myopathy, but segregation data is limited and it is unknown whether this individual was screened for variants in other genes associated with myopathy (Klein et al., 2011); 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: 22473935, 20681998, 25370123, 31951399, 32899693, 35693006, 35081925, 21911697)
Neuberg Centre For Genomic Medicine, NCGM	RCV003338423	SCV004048260	uncertain significance	Central core myopathy		criteria provided, single submitter	clinical testing	The missense variant c.3494G>A (p.Gly1165Asp) in RYR1 gene has been observed in individual(s) with clinical features of congenital myopathy (Klein A et.al.,2011). This variant has been reported to the ClinVar database as Uncertain Significance. The p.Gly1165Asp variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.001988% is reported in gnomAD. The amino acid Gly at position 1165 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gly1165Asp in RYR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance .