Submissions for variant NM_000540.3(RYR1):c.6418C>T (p.Arg2140Trp)

gnomAD frequency: 0.00005  dbSNP: rs750275456

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522618	SCV000619375	likely pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	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: 12668474, 33767344, 30611313, 33176865)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001295204	SCV001484117	uncertain significance	RYR1-related disorder	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 2140 of the RYR1 protein (p.Arg2140Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs750275456, ExAC 0.006%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related conditions (PMID: 30611313). ClinVar contains an entry for this variant (Variation ID: 450761). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000522618	SCV003810517	uncertain significance	not provided	2020-07-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001295204	SCV004117351	uncertain significance	RYR1-related disorder	2022-09-22	criteria provided, single submitter	clinical testing	The RYR1 c.6418C>T variant is predicted to result in the amino acid substitution p.Arg2140Trp. This variant has been reported in the compound heterozygous state in two individuals with presumed RYR1-related myopathies (Garibaldi et al 2019. PubMed ID: 30611313). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38985135-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003616	SCV004820877	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2140 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar Variation ID: 450761). This variant has been identified in 7/250448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.