ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.1885G>C (p.Val629Leu) (rs185511111)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000188010 SCV000613881 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
Bioinformatics Core,Luxembourg Center for Systems Biomedicine RCV000656018 SCV000588294 pathogenic Rolandic epilepsy 2017-01-01 no assertion criteria provided case-control CAADphred>15
Fulgent Genetics,Fulgent Genetics RCV000765988 SCV000897420 uncertain significance Benign familial neonatal seizures 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000767106 SCV000241613 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing The V629L 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, and it was not observed with any significant frequency in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V629L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000471330 SCV000543214 uncertain significance Benign familial neonatal seizures 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 629 of the KCNQ3 protein (p.Val629Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs185511111, ExAC 0.009%). This variant has been observed in an individual affected with rolandic epilepsy and in a control individual (PMID: 29358611). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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