ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4186G>A (p.Ala1396Thr)

gnomAD frequency: 0.00001  dbSNP: rs772111760
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001352038 SCV001546561 uncertain significance RYR1-related disorder 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1396 of the RYR1 protein (p.Ala1396Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs772111760, ExAC 0.003%). 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: 1047339). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

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