ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.418G>A (p.Ala140Thr) (rs142474192)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000655545 SCV000777476 uncertain significance RYR1-Related Disorders 2018-07-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 140 of the RYR1 protein (p.Ala140Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs142474192, ExAC 0.02%). This variant has been reported in an individual with suspected familial malignant hyperthermia (PMID: 21455645). ClinVar contains an entry for this variant (Variation ID: 544412). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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 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.
PreventionGenetics RCV000721524 SCV000852607 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing

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