Submissions for variant NM_000540.3(RYR1):c.2113G>A (p.Gly705Arg)

gnomAD frequency: 0.00001  dbSNP: rs565825739

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001334521	SCV001527388	uncertain significance	Central core myopathy	2018-05-16	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002499657	SCV002777176	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-08-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003591856	SCV004297327	pathogenic	RYR1-related disorder	2023-05-19	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 1032420). This missense change has been observed in individual(s) with autosomal recessive RYR1-related conditions (PMID: 27616680). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs565825739, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 705 of the RYR1 protein (p.Gly705Arg).
All of Us Research Program, National Institutes of Health	RCV004005144	SCV004831568	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 705 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia susceptibility but has been reported in individuals with myopathy (PMID: 22473935, 23394784, 25476234, 25476234). This variant has been identified in 2/248930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance fro autosomal dominant malignant hyperthermia susceptibility.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702096	SCV001930574	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702096	SCV001959943	likely pathogenic	not provided		no assertion criteria provided	clinical testing