ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10577C>T (p.Ala3526Val)

gnomAD frequency: 0.00004  dbSNP: rs374061380
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000548666 SCV000659752 uncertain significance RYR1-related disorder 2022-05-21 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3526 of the RYR1 protein (p.Ala3526Val). This variant is present in population databases (rs374061380, gnomAD 0.005%). 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: 478154). 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 not expected to disrupt RYR1 protein function. 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.
Illumina Laboratory Services, Illumina RCV001270828 SCV001451594 uncertain significance Central core myopathy 2019-03-05 criteria provided, single submitter clinical testing The RYR1 c.10562C>T (p.Ala3521Val) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.000031 in the European (Non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Ala3521Val variant is classified as a variant of uncertain significance for central core disease.
Fulgent Genetics, Fulgent Genetics RCV002506376 SCV002815264 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 2021-10-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586797 SCV005077259 uncertain significance not specified 2024-04-18 criteria provided, single submitter clinical testing Variant summary: RYR1 c.10577C>T (p.Ala3526Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251200 control chromosomes (gnomAD v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.10577C>T in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 478154). Based on the evidence outlined above, the variant was classified as uncertain significance.

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