ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 27861786). 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 expected to disrupt KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 205867). This missense change has been observed in individual(s) with early-onset epilepsy in infancy (PMID: 27861786, 29390993). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 198 of the KCNQ2 protein (p.Arg198Gln).

Criteria applied: PS2_VSTR,PS3_MOD,PM1,PM2_SUP,PP3

PM1_strong;PP5_strong;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants have been shown to have gain of function effects, whilst many NMD-predicted variants with loss of function effects have been reported (PMID 24318194; ClinVar). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (PMID 24318194). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Ion transport domain). (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported de novo in individuals with infantile spasms without prior neonatal seizures (ClinVar; PMID 27861786). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies with this variant showed gain of function effects on channel function (PMID 27861786). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

KCNQ2 NM_172107.3 exon 4 p.Arg198Gln (c.593G>A): This variant has been reported in the literature as de novo in at least 4 individuals with infantile spasms and hypsarrhythmia (Millichap 2017 PMID:27861786). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:205867). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, splice prediction tools strongly predict the creation of a new acceptor site; however, further studies are needed to understand its impact. Functional studies also support this variant may impact the protein, potentially creating a gain of function (Millichap 2017 PMID:27861786). In summary, this variant is classified as pathogenic.

Published functional studies demonstrate that the R198Q substitution alters voltage gating of the channel (Miceli et al., 2008; Millichap et al., 2016); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18515377, 31965297, 29655203, 31440733, 27861786, 29390993, 32506321, 29129156, 29455050, 33951346, 34163418, 31440721)