ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.2128T>C (p.Tyr710His) (rs181746838)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187990 SCV000241593 uncertain significance not provided 2016-01-28 criteria provided, single submitter clinical testing The Y710H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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; however, the 1000 Genomes Project reports Y710H was observed in 2/186 (1%) alleles from individuals of Chinese Dai background, indicating it may be a rare (benign) variant in this population. The Y710H 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. 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 RCV000525504 SCV000649485 uncertain significance Benign familial neonatal seizures 2018-04-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 710 of the KCNQ3 protein (p.Tyr710His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs181746838, ExAC 0.09%) but has not been reported in the literature in individuals with a KCNQ3-related disease. ClinVar contains an entry for this variant (Variation ID: 205984). 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 is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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