ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4861G>A (p.Glu1621Lys)

dbSNP: rs1398897130
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001948933 SCV002215933 uncertain significance RYR1-related disorder 2023-06-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1621 of the RYR1 protein (p.Glu1621Lys). This variant is not present in population databases (gnomAD no frequency). 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: 1438275). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003994363 SCV004813648 uncertain significance not specified 2024-02-20 criteria provided, single submitter clinical testing Variant summary: RYR1 c.4861G>A (p.Glu1621Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 184464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.4861G>A has not been reported in the literature in individuals affected with Myopathy, RYR1-Associated. The following publication has been ascertained in the context of this evaluation (PMID: 30930780). ClinVar contains an entry for this variant (Variation ID: 1438275). Based on the evidence outlined above, the variant was classified as uncertain significance.

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