ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10531G>A (p.Val3511Met)

dbSNP: rs376389988
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001933847 SCV002202171 uncertain significance RYR1-related disorder 2024-04-29 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 3511 of the RYR1 protein (p.Val3511Met). This variant is present in population databases (rs376389988, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. 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: 1427713). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. 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.
Revvity Omics, Revvity RCV003130614 SCV003813128 uncertain significance not provided 2021-10-16 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004010918 SCV004824047 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-10-30 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 3511 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 8/251374 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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