ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13190C>G (p.Ala4397Gly) (rs1057520588)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443374 SCV000516182 likely benign not specified 2015-04-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000696501 SCV000825064 uncertain significance RYR1-Related Disorders 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 4397 of the RYR1 protein (p.Ala4397Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 379371). 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: "Tolerated"; PolyPhen-2: "Not Available"; 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: 16917943, 12565913, 23919265). 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. 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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