ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.1216G>A (p.Val406Ile) (rs144474368)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187974 SCV000241577 uncertain significance not specified 2017-04-04 criteria provided, single submitter clinical testing The V406I variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species and Isoleucine is observed at this position in several species in evolution. The V406I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, the V406I variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000647893 SCV000769698 uncertain significance Benign familial neonatal seizures 2018-01-02 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 406 of the KCNQ3 protein (p.Val406Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs144474368, ExAC 0.01%). This variant has not been reported in the literature in individuals with KCNQ3-related disease. ClinVar contains an entry for this variant (Variation ID: 205969). 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.
Ambry Genetics RCV000720908 SCV000851792 likely benign Seizures 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Does not segregate with disease in family study (genes with incomplete penetrance)

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