ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.11731A>G (p.Thr3911Ala)

gnomAD frequency: 0.00001  dbSNP: rs200622493
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000209970 SCV000265743 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Invitae RCV001518854 SCV001727628 benign RYR1-related disorder 2024-01-28 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001518854 SCV004741333 uncertain significance RYR1-related disorder 2023-11-17 criteria provided, single submitter clinical testing The RYR1 c.11731A>G variant is predicted to result in the amino acid substitution p.Thr3911Ala. This variant was reported as a variant of uncertain significance in a cohort study of an unselected population for identification of malignant hyperthermia susceptibility (Supplement 3, Gonsalves et al. 2013. PubMed ID: 24195946). This variant is reported in 0.072% of alleles in individuals of South Asian descent, including one homozygote, in gnomAD (http://gnomad.broadinstitute.org/variant/19-39034028-A-G). Other amino acid substitutions near the p.Thr3911 residue have been reported to be causative for RYR1-related disorders (Human Gene Mutation Database). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV000209970 SCV004821744 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 3911 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 not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 27/251492 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.
GeneDx RCV004589903 SCV005078141 uncertain significance not provided 2024-04-28 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

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