Submissions for variant NM_000540.3(RYR1):c.6445G>A (p.Val2149Met)

gnomAD frequency: 0.00001  dbSNP: rs776830747

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813191	SCV000953536	uncertain significance	RYR1-related disorder	2024-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2149 of the RYR1 protein (p.Val2149Met). This variant is present in population databases (rs776830747, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 656707). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729710	SCV001976951	likely pathogenic	Central core myopathy	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PP2, PP3, PP4
Revvity Omics, Revvity	RCV003132080	SCV003810506	uncertain significance	not provided	2019-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV003132080	SCV004035696	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Reported in a patient referred for whole exome sequencing who also harbored a missense variant in the RYR1 gene in trans (Marinakis et al., 2021); however, detailed clinical information was not provided; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12668474, 34008892)
PreventionGenetics, part of Exact Sciences	RCV000813191	SCV004114760	uncertain significance	RYR1-related disorder	2022-12-13	criteria provided, single submitter	clinical testing	The RYR1 c.6445G>A variant is predicted to result in the amino acid substitution p.Val2149Met. This variant was reported in the compound heterozygous state in an individual with an an autosomal recessive RYR1-related disorder (Table S3, Marinakis et al. 2021. PubMed ID: 34008892). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38985162-G-A). 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	RCV004001749	SCV004820879	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 2149 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function. 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: 656707). This variant has been identified in 7/282122 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056593	SCV005726635	uncertain significance	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6445G>A (p.Val2149Met) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250732 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6445G>A has been reported in the literature in at-least one compound heterozygous individual affected with Neuromuscular disease (example: Marinakis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Multicore Myopathy With External Ophthalmoplegia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34008892). ClinVar contains an entry for this variant (Variation ID: 656707). Based on the evidence outlined above, the variant was classified as uncertain significance.