ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.3301G>A (p.Val1101Met) (rs145088074)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV000785928 SCV000924507 likely pathogenic Myopathy, Central Core 2018-06-15 criteria provided, single submitter research The heterozygous p.Val1101Met variant was identified by our study in the compound heterozygous state, along with another likely pathogenic variant, in one individual with central core disease. This variant has been identified in <0.01% (1/34420) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145088074). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The Valine (Val) at position 1101 is highly conserved in mammals and evolutionarily distant species, raising the possibility that a change at this position may not be tolerated. Computational tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.
GeneDx RCV000182605 SCV000234964 uncertain significance not provided 2016-05-13 criteria provided, single submitter clinical testing The V1101M variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1101M variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V1101M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V1101M as a variant of uncertain significance.

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