ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.2383G>A (p.Val795Ile) (rs764544537)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187999 SCV000241602 uncertain significance not provided 2017-04-10 criteria provided, single submitter clinical testing p.Val795Ile (GTC>ATC): c.2383 G>A in exon 15 of the KCNQ3 gene (NM_004519.2) The Val795Ile missense change 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 amino acid substitution is conservative as both Valine and Isoleucine are uncharged, non-polar amino acid residues. However, Val795Ile alters a conserved position in the C-terminal region of the KCNQ3 protein and in silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Val795Ile is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000532568 SCV000649488 uncertain significance Benign familial neonatal seizures 2017-11-10 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 795 of the KCNQ3 protein (p.Val795Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs764544537, ExAC 0.01%). This variant has not been reported in the literature in individuals with a KCNQ3-related disease. ClinVar contains an entry for this variant (Variation ID: 205993). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on KCNQ3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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