ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.915C>G (p.Phe305Leu) (rs775918190)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000533623 SCV000634080 pathogenic Early infantile epileptic encephalopathy 2018-03-08 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 305 of the KCNQ2 protein (p.Phe305Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNQ2-related disease. However, family studies have indicated that this variant was not present in the parents of an individual with KCNQ2-related disease, which suggests that it was de novo in that affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 461423). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). A different variant (c.913T>C) giving rise to the same protein effect observed here (p.Phe305Leu) has been reported in 2 individuals affected with early infantile epileptic encephalopathy (PMID: 25473036, 27779742). In at least one of these individuals, the variant arose de novo. This indicates that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.

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