ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13912G>A (p.Gly4638Ser) (rs118192136)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000056190 SCV000087279 pathologic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000687662 SCV000815246 likely pathogenic RYR1-Related Disorders 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 4638 of the RYR1 protein (p.Gly4638Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with central core disease (PMID: 16621918) and in two individuals with congenital myopathy (PMID: 23394784), as well as one individual with limb-girdle muscular dystrophy or LGMD (Invitae). ClinVar contains an entry for this variant (Variation ID: 65943). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. Variants that disrupt the p.Gly4638 amino acid residue in RYR1 have been observed in affected individuals (PMID:23553787, 12565913, 14985404, 16917943). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119489 SCV000154396 not provided not provided no assertion provided not provided

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