ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.2465C>T (p.Ala822Val) (rs796052661)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187936 SCV000241538 uncertain significance not provided 2014-09-12 criteria provided, single submitter clinical testing p.Ala822Val (A822V) GCG>GTG: c.2465 C>T in exon 17 of the KCNQ2 gene (NM_172107.2) The A822V variant has not been published as a mutation, nor has it been reported as a benign polymorphism 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 A822V 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 in mammals and 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 mutation or a rare benign variant.The identification of A822V suggests that A822V may be a benign variant not associated with the child's phenotype; however, the possibility that it is a disease-associated mutation cannot be excluded since some individuals with KCNQ2 mutations never develop seizures due to incomplete penetrance. Therefore, the identification of A822V in this unaffected parent does not clarify the clinical significance of the variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV000791538 SCV000930793 uncertain significance Early infantile epileptic encephalopathy 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 822 of the KCNQ2 protein (p.Ala822Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNQ2-related disease. ClinVar contains an entry for this variant (Variation ID: 205934). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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