ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.1471G>A (p.Gly491Arg) (rs201552546)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000389265 SCV000329371 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNQ3 gene. The G491R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G491R variant is observed in 12/64,692 (0.02%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with KCNQ3-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000704485 SCV000833436 uncertain significance Benign familial neonatal seizures 2018-03-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 491 of the KCNQ3 protein (p.Gly491Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201552546, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with KCNQ3-related disease. ClinVar contains an entry for this variant (Variation ID: 279818). 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 disruptive, 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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