ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.650T>C (p.Val217Ala) (rs749876289)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481269 SCV000573820 uncertain significance not provided 2017-03-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANO5 gene. The c.650 T>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.650 T>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.650 T>C may damage the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.650 T>C does not alter splicing, it will result in the V217A missense change. The V217A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000816761 SCV000957285 uncertain significance Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 217 of the ANO5 protein (p.Val217Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs749876289, ExAC 0.002%). This variant has not been reported in the literature in individuals with ANO5-related disease. ClinVar contains an entry for this variant (Variation ID: 424043). 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: "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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