ClinVar Genomic variation as it relates to human health

This study shows that diverse genetic causes underlie CVI.

The de novo missense variant c.688C>T, p.Arg230Cys identified in this individual has been reported as de novo variant in several patients with Neurodevelopmental disability (nonverbal, with autism spectrum disorder or autistic features and multifocal status epilepticus during sleep) [PMID: 31177578].The p.Arg230Cys is situated in the mutational hotspot of KCNQ3 gene, and functional studies indicate that it causes a gain-of-function stabilization of the ion channel's activated state [PMID: 31177578; PMID: 25740509]. Patients with p.Arg230Cys variant are usually ambulatory by 2 years of age, but were either nonverbal or had single words only and were cognitively impaired with ASD or autistic features [PMID: 31177578; PMID: 31238879].This variant is also not reported in gnomAD database, indicating this is a rare allele. Based on the available evidence, the de novo missense variant c.688C>T, p.Arg230Cys in the KCNQ3 gene is classified as pathogenic.

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.

The KCNQ3 c.688C>T (p.Arg230Cys) variant is a missense variant that has a well-documented association with KCNQ3-related disorders. Across a selection of the available literature, it has been reported in at least eight individuals with features that included intellectual disability, autism, EEG abnormalities, seizures, staring spells, strabismus, hypotonia, and structural abnormalities on brain MRI (Rauch et al. 2012; Epi4K Consortium et al. 2013; Deciphering Developmental Disorders Study 2017; Geisheker et al. 2017; Lindy et al. 2018; Trinh et al. 2019; Sands et al. 2019; Valentino et al. 2021). In at least four of these individuals, the variant occurred de novo. The p.Arg230Cys variant is not reported in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest the variant is rare. In vitro analyses have demonstrated that this variant, which affects a crucial gating residue in the S4 transmembrane segment, stabilizes the activated state of the channel, allowing current to flow throughout the physiological voltage range and resulting in gain of function (Miceli et al. 2015; Barro-Soria 2019; Sands et al. 2019). Additional amino acid changes affecting this residue have also been reported in association with KCNQ3-related disorders (Landrum et al. 2016). Based on the available evidence, the p.Arg230Cys variant is classified as pathogenic for KCNQ3-related disorders.

Published functional studies demonstrate a gain-of-function stabilization of the ion channel's activated state (Miceli et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23020937, 26350515, 25740509, 31036916, 31238879, 23934111, 28628100, 28135719, 29655203, 28191890, 31177578, 31618753, 31981491, 31175295, 31785789, 33004838, 27535533)

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the KCNQ3 protein (p.Arg230Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurodevelopmental disorders and early-onset epileptic encephalopathy (PMID: 23020937, 23934111, 26350515, 28135719, 28628100, 29655203). In at least one individual the variant was observed to be de novo. This variant is also known as p.Arg110Cys, g.133192493G>A. ClinVar contains an entry for this variant (Variation ID: 205963). 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 KCNQ3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNQ3 function (PMID: 25740509, 30578330). For these reasons, this variant has been classified as Pathogenic.

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP3 supporting

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with benign neonatal seizures 2 (MIM#121201) and neurodevelopmental disorder (MONDO:0700092), KCNQ3-related, respectively. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been noted for benign neonatal seizures 2 (MIM#121201) (PMID: 24851285). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic/pathogenic in more than ten individuals, with five reports stating the variant was de novo (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Many functional analyses on this variant, R230C, have shown that this is a crucial gating residue in the S4 transmembrane segment where the variant stabilises the activated state of the channel, resulting in a gain of function effect (PMIDs: 31177578, 30578330, 25740509). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant interpretted as Pathogenic and reported on 10-08-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Variant found in 4 unrelated persons, all de novo, in studies focused on different phenotypes