ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.1955A>G (p.Tyr652Cys) (rs563666662)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498435 SCV000589656 likely pathogenic not provided 2016-03-16 criteria provided, single submitter clinical testing The Y652C variant has been previously reported in two compound heterozygous siblings with limb-girdle muscular dystrophy (van der Kooi et al., 2013). It was not observed 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 Y652C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000691138 SCV000818881 uncertain significance Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 652 of the ANO5 protein (p.Tyr652Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with limb-girdle muscular dystrophy in a family (PMID: 23607914). ClinVar contains an entry for this variant (Variation ID: 432005). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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