Submissions for variant NM_000540.3(RYR1):c.9859C>T (p.Arg3287Cys)

gnomAD frequency: 0.00004  dbSNP: rs201276068

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000655563	SCV000777494	uncertain significance	RYR1-related disorder	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3287 of the RYR1 protein (p.Arg3287Cys). This variant is present in population databases (rs201276068, gnomAD 0.09%). 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: 544426). 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.
PreventionGenetics, part of Exact Sciences	RCV000721760	SCV000852895	uncertain significance	not provided	2015-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307581	SCV002600766	likely benign	not specified	2022-10-28	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.9859C>T (p.Arg3287Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 280070 control chromosomes (gnomAD), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype (8.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.9859C>T has been reported in the literature in individuals without history of adverse anesthetic events (van den Bersselaar_2022) and in an individual affected with congenital myopathy (Gonorazky_2019). These reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV002499131	SCV002780281	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	2021-08-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721760	SCV003814414	uncertain significance	not provided	2020-07-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000721760	SCV005078471	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	Observed in a proband with centronuclear myopathy who also harbored a second RYR1 pathogenic variant; however segregation studies to determine phase were not provided (PMID: 30827497); Previously reported in a individual from a cohort of patients referred for malignant hyperthermia testing; however clinical details were not provided (PMID: 35285867); 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: 34426522, 35285867, 30827497)