Submissions for variant NM_000540.3(RYR1):c.10492C>G (p.Arg3498Gly)

gnomAD frequency: 0.00006  dbSNP: rs201358408

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210009	SCV000265736	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Invitae	RCV000805178	SCV000945125	uncertain significance	RYR1-related disorder	2022-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 3498 of the RYR1 protein (p.Arg3498Gly). This variant is present in population databases (rs201358408, gnomAD 0.008%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 24195946). ClinVar contains an entry for this variant (Variation ID: 224398). 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.
GeneDx	RCV001589104	SCV001824591	uncertain significance	not provided	2020-11-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified via exome sequencing in a volunteer not ascertained for malignant hyperthermia susceptibility (MHS) who was found to have a three generation family history of MHS; however, the variant did not segregate with the phenotype in the family (Gonsalves et al., 2013); This variant is associated with the following publications: (PMID: 24195946)
Fulgent Genetics, Fulgent Genetics	RCV002478757	SCV002782484	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	2021-08-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001589104	SCV003812433	uncertain significance	not provided	2021-05-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000210009	SCV004820980	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 3498 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 been reported in a family affected with malignant hyperthermia susceptibility, but the variant did not co-segregate with disease (PMID: 24195946). This variant has been identified in 8/282550 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.