Submissions for variant NM_172107.4(KCNQ2):c.2117C>A (p.Ala706Asp)

gnomAD frequency: 0.00001  dbSNP: rs980128101

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001884599	SCV002161738	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 706 of the KCNQ2 protein (p.Ala706Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1393693). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ2 protein function. 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.
GeneDx	RCV002272522	SCV002558139	uncertain significance	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282636	SCV002572186	uncertain significance	not specified	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: KCNQ2 c.2117C>A (p.Ala706Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 150982 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2117C>A in individuals affected with KCNQ2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.