ClinVar Miner

Submissions for variant NM_004974.4(KCNA2):c.1195G>A (p.Val399Met) (rs1064794738)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483386 SCV000569839 likely pathogenic not provided 2017-08-28 criteria provided, single submitter clinical testing The V399M variant in the KCNA2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V399M variant 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. This substitution occurs at a position within the helical transmembrane domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (P405L) has been reported in the Human Gene Mutation Database in association with epileptic encephalopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the V399M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The V399M variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000723323 SCV000854717 likely pathogenic Epileptic encephalopathy, early infantile, 32 2018-06-26 no assertion criteria provided clinical testing

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