ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate that p.(A421V) significantly affects Kv3.1 potassium channel function (Park et al., 2019; Cameron et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31216804, 32695065, 31785789, 33349918, Zhang2020[casereport], 33735526, 35618197, 31932120, 34733949, 33725338, 35840580, 34448338, 32655623, 31353862, 31353855)

Variant summary: KCNC1 c.1262C>T (p.Ala421Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250990 control chromosomes. c.1262C>T, arising de novo, has been reported in the literature in multiple individuals affected with Epilepsy or Progressive Myoclonic Epilepsy 7 (examples, Kim_2021, Cameron_2019, Park_2019, Zhang_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, both of which suggest a loss-of-function effect of this variant (Cameron_2019, Park_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31353855, 33349918, 31353862, 31216804). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This missense change has been observed in individual(s) with clinical features of KCNC1-related disorder (PMID: 31353855, 31353862). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNC1 function (PMID: 31353855, 31353862). 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 KCNC1 protein function. ClinVar contains an entry for this variant (Variation ID: 488536). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the KCNC1 protein (p.Ala421Val).

The observed missense variant c.1262C>T(p.Ala421Val) in KCNC1 gene has been reported previously in heterozygous state in multiple individuals with KCNC1-related disorders (Cameron JM, et al., 2019, Park J, et al., 2019). Experimental studies have shown that this missense change affects KCNC1 function (Cameron JM, et al., 2019). The c.1262C>T variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic (multiple submissions). The amino acid Alanine at position 421 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ala421Val in KCNC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.