ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1930G>A (p.Asp644Asn) (rs1554438576)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520134 SCV000621758 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing The c.1930 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1930 G>A variant is not observed in large population cohorts (Lek et al., 2016). Multiple in-silico splice prediction models predict that c.1930 G>A destroys the natural splice donor site and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.1930 G>A on splicing in this individual is unknown. If c.1930 G>A does not alter splicing, it will result in the D644N missense change. The D644N substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. However, this variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (V640G, M646V/I) have been reported in the Human Gene Mutation Database in association with myotonia congenita (Stenson et al., 2014), supporting the functional importance of this region of the protein.

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