ClinVar Genomic variation as it relates to human health

The R210H pathogenic variant has been reported multiple times as a de novo change in individuals with epileptic encephalopathy (Weckhuysen et al., 2013; Pisano et al., 2015; Reid et al., 2016). The R210H variant is not observed in large population cohorts (Lek et al., 2016). The R210H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, a different missense variant in the same residue (R210C) as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider R210H to be a pathogenic variant.

The p.Arg210His variant has been reported as a de novo change in multiple individuals with epileptic encephalopathy (PMID: 24107868, 24371303, 25880994, 26446091). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The p.Arg210His variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This substitution is predicted to be within the transmembrane segment S4 voltage sensor. Functional studies have demonstrated that the p.Arg210His variant disrupts the normal channel conductance activity of the KCNQ2 protein (PMID: 28283543). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.629G>A (p.Arg210His) variant is classified as Pathogenic.

This heterozygous mis-sense variant identified in 1 month female with neonatal onset of seizures from day 1, encephalopathy and abnormal EEG . This variant is absent from gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.85. Based on the familial segregation is was found to be a “de-novo” variant. There is a clinvar entry [Variation ID: 279931] for this variant with a Pathogenic interpretation by multiple submitters [PP5]. PMID [26446091]

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 210 of the KCNQ2 protein (p.Arg210His). 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, 24371303, 25880994, 26446091). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279931). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 28283543). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with epileptic encephalopathy, early infantile, 7 (MIM#613720). Missense have been reported with a dominant negative mechanism, causing both early infantile epileptic encephalopathy and benign neonatal seizures (OMIM, PMID 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Some variants have been reported with both severe infantile onset epileptic encephalopathy and milder benign seizures (OMIM) (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes (p.Arg210Pro, p.Arg210Cys) have been reported in several de novo patients with infantile onset epileptic encephalopathy (ClinVar, PMID: 25818041). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple de novo patients with infantile onset epileptic encephalopathy (ClinVar, PMID: 24107868, PMID: 24371303, PMID: 26446091). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

EE (epileptic encephalopathy)