ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187884 SCV000241486 pathogenic not provided 2013-02-05 criteria provided, single submitter clinical testing p.Phe305Leu (TTC>TTA): c.915 C>A in exon 6 of the KCNQ2 gene (NM_172107.2)The Phe305Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Phe305Leu in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative as both Phenylalanine and Leucine are uncharged, non-polar amino acid residues. However, Phe305Leu alters a conserved position in a transmembrane domain in the KCNQ2 protein and other missense mutations in this region of the protein have been identified in patients with benign familial neonatal seizures (Steinlein et al., 2007; Singh et al., 1998). In addition, multiple in-silico algorithms predict it may be damaging to the structure/function of the protein. Therefore, based on the currently available information, Phe305Leu is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s).
Invitae RCV001059171 SCV001223784 likely pathogenic Early infantile epileptic encephalopathy 2019-03-25 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 been observed in an individual affected with neonatal epileptic encephalopathy (PMID: 24107868). ClinVar contains an entry for this variant (Variation ID: 205887). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant (c.913T>C) giving rise to the same protein effect observed here (p.Phe305Leu) has been determined to be pathogenic (PMID:27779742, 25473036). This suggests that this variant is also likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews RCV000678151 SCV000484594 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)

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