ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4910C>T (p.Ala1637Val)

gnomAD frequency: 0.00009  dbSNP: rs569890286
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691956 SCV000819757 uncertain significance RYR1-related disorder 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1637 of the RYR1 protein (p.Ala1637Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs569890286, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. 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: "Probably Damaging"; 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 RCV001771954 SCV002002048 uncertain significance not provided 2020-06-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002493179 SCV002790899 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 2022-01-10 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999570 SCV004830736 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-10 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 1637 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 RYR1-related disorders in the literature. This variant has been identified in 7/192272 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.

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