ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.875T>C (p.Leu292Pro) (rs1060500602)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471825 SCV000543194 likely pathogenic Early infantile epileptic encephalopathy 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 292 of the KCNQ2 protein (p.Leu292Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy and has also been observed in cis with a second adjacent missense variant in an individual with epilepsy and/or neurodevelopmental disease (PMID: 29644095, 29655203). ClinVar contains an entry for this variant (Variation ID: 405208). 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: "Benign"; Align-GVGD: "Class C65"). 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853366 SCV000996235 likely pathogenic Early infantile epileptic encephalopathy 7 2019-01-18 criteria provided, single submitter clinical testing The c.875T>C (p.Leu292Pro) is a missense variant. This variant has not been reported in the literature. However, a variant classified as likely pathogenic has been reported in ClinVar at the same amino acid position (https://www.ncbi.nlm.nih.gov/clinvar/RCV000187943.1/). Additionally, this amino acid position lies within an established functional domain in KCNQ2. Multiple established pathogenic variants in KCNQ2 immediately surround position 292 (PMID: 24318194, 26007637; http://www.rikee.org/enter-kcnq2-variant-database). The variant is predicted to be damaging by in silico algorithms and is well conserved through evolution. Based on the combined evidence, this variant is classified as likely pathogenic.

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