ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.776A>G (p.Asp259Gly) (rs1057518489)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412840 SCV000492178 likely pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing A novel D259G variant that is likely pathogenic has been identified in the KCNQ2 gene. The D259G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. 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 D259G 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. This substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. This substitution is predicted to be within the extracellular loop between the 5th and 6th transmembrane domains, and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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