ClinVar Genomic variation as it relates to human health

Previously reported in a 20-year-old male with SUD and a history of two syncopal episodes; however, no premortem ECG was available and familial segregation studies were declined (PMID: 22457051); Published functional studies demonstrated p.(V392I) significantly increased peak current density compared to wild type and slowed recovery from inactivation, suggestive of a mixed electrophysiological phenotype (PMID: 22457051); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23400760, 34426522, 34361012, 30662450, 32921676, 32901917, 30776697, 34709746, Ahammed2023[Review], 36376730, 33920294, 35861988, 35388935, 35813061, 22457051)

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individual and observed (PMID: 30776697, PS2). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.836, 3Cnet: 0.893, PP3). Patient's phenotype is considered compatible with KCND3-related seizure disorder.Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

ClinVar contains an entry for this variant (Variation ID: 192255). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCND3 function (PMID: 22457051). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCND3 protein function. This missense change has been observed in individual(s) with autosomal dominant KCND3-related conditions and/or sudden unexplained death or non-syndromic epileptic encephalopathy (PMID: 22457051, 30776697, 32921676). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 392 of the KCND3 protein (p.Val392Ile).

The KCND3 c.1174G>A variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE (PS4_Supporting, PM2, PP3) The KCND3 c.1174G>A variant is a single nucleotide change in exon 3/8 of the KCND3 gene, which is predicted to change the amino acid valine at position 392 in the protein to isoleucine. This variant has been reported as a de novo change in a 5yo boy with seizures, psychomotor regression and vision impairment (PMID:30776697) (PS4_Supporting). This variant has been reported in dbSNP (rs786205867) but is absent from population databases (PM2). This variant has been reported as pathogenic, likely pathogenic and VUS by other diagnostic laboratories (ClinVar Variation ID: 192255). it has also been reported as damaging in the HGMD disease database for Epileptic encephalopathy, Brugada syndrome and sudden unexplained death syndrome (CM124831). Computational predictions support a deleterious effect on the gene or gene product (PP3).