Submissions for variant NM_000540.3(RYR1):c.3619G>A (p.Val1207Met)

gnomAD frequency: 0.00006  dbSNP: rs760235443

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655555	SCV000777486	uncertain significance	RYR1-related disorder	2022-09-19	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 1207 of the RYR1 protein (p.Val1207Met). This variant is present in population databases (rs760235443, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 30611313). ClinVar contains an entry for this variant (Variation ID: 544419). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 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.
Athena Diagnostics	RCV000712949	SCV000843509	uncertain significance	not provided	2018-07-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477468	SCV002781419	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	2021-07-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000712949	SCV003810553	uncertain significance	not provided	2021-05-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333094	SCV004040996	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712949	SCV004141590	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	RYR1: PM2:Supporting, PM3:Supporting, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488773	SCV004241331	uncertain significance	not specified	2023-12-19	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.3619G>A (p.Val1207Met) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251420 control chromosomes (i.e., 32 alleles, no homozygotes; gnomAD v2.1.1. Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3619G>A has been reported in the literature in at least one compound heterozygous individual affected with core-rod myopathy (e.g., Garibaldi_2019) and one homozygous individual affected with distal arthrogryposis (e.g., Shamseldin_2021). These data indicate that the variant may be associated with autosomal recessive disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding an 80% reduction in RyR1 protein levels in a muscle biopsy from a compound heterozgyous patient relative to the control; this finding does not allow convincing conclusions about the variant effect as the measurement was conducted only in the presence of a second RYR1 variant (e.g., Garibaldi_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 24627108, 34645488, 34316023). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989571	SCV004806726	uncertain significance	Central core myopathy	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003333094	SCV004820815	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1207 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 autosomal dominant malignant hyperthermia in the literature, although it has been observed in individuals affected with other phenotype(s) (ClinVar Variation ID: 544419; PMID: 30611313). This variant has been identified in 34/282788 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.