ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the KCNQ2 protein (p.Arg201Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 24107868, 27535030, 28133863, 28687180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205869). 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. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 25740509). This variant disrupts the p.Arg201 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187, 25880994, 28139826, 29190809). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant is interpreted as a Pathogenic, for Epileptic encephalopathy, early infantile, 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Loss of voltage-dependent channel gating and increased channel activation, gain-of-function mutation (PMID:25740509). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:26993267,28133863,24107868,28687180). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28687180).

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000205869, PMID:24107868). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27535030). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000369753, PMID:23708187). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.931>=0.6, 3CNET: 0.997>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The missense variant c.601C>T (p.Arg201Cys) in the KCNQ2 gene has been reported in heterozygous state in an individual affected with early onset epileptic encephalopathy (Hortigüela M. et al., 2017). Experimental studies have shown that this missense change stabilized the activated state of the channel, thereby producing gain-of function (Miceli F. et al., 2015). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes databases. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Uncertain Significance. The amino acid Arginine at position 201 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a gain-of-function (Miceli et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28687180, 25740509, 27535030, 28133863, 28867141, 24107868, 28139826, 32917465)

Likely pathogenicity based on finding it once in our laboratory de novo in a 6-month-old female with motor delays, hypotonia, epilepsy (clinically thought to be early infantile myoclonic encephalopathy, onset at day 2 of life, with apneic episodes, controlled by medication but with onset of myoclous), nystagmus

EE (epileptic encephalopathy)