ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.128C>T (p.Ala43Val) (rs749554385)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000715904 SCV000846736 likely benign Seizures 2016-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Does not segregate with disease in family study (genes with incomplete penetrance)
GeneDx RCV000187941 SCV000241544 uncertain significance not provided 2015-08-26 criteria provided, single submitter clinical testing p.Ala43Val (GCC>GTC): c.128 C>T in exon 1 of the KCNQ2 gene (NM_172107.2) A variant of unknown significance has been identified in the KCNQ2 gene. The A43V 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 5,000 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 A43V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000817367 SCV000957922 uncertain significance Early infantile epileptic encephalopathy 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 43 of the KCNQ2 protein (p.Ala43Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. While this variant is present in population databases (rs749554385), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNQ2-related disease. ClinVar contains an entry for this variant (Variation ID: 205939). 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: "Deleterious"; PolyPhen-2: "Possibly 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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