Submissions for variant NM_004975.4(KCNB1):c.1223C>G (p.Pro408Arg)

dbSNP: rs2146813607

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002045029	SCV002296666	uncertain significance	Developmental and epileptic encephalopathy, 26	2022-08-23	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 KCNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 1501897). This variant has not been reported in the literature in individuals affected with KCNB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 408 of the KCNB1 protein (p.Pro408Arg).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV002045029	SCV005900684	likely pathogenic	Developmental and epileptic encephalopathy, 26	2024-01-06	criteria provided, single submitter	clinical testing	The KCNB1 gene is constrained against variation (Z-score= 4.27 and pLI = 1), and missense variants are a common mechanism of disease (PMID: 28806457, 25164438, 26477325, 36618935). The c.1223C>G (p.Pro408Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has not been previously reported or functionally characterized in the literature to our knowledge. A different amino acid change at the same residue (p.Pro408Ser) has been previously reported in individuals with early infantile epileptic encephalopathy (PMID: 31054490, 35071126). The c.1223C>G (p.Pro408Arg) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant. These results indicate that this variant likely arose as a post-zygotic de novo event in this individual. Based on the available evidence, c.1223C>G (p.Pro408Arg) is classified as Likely Pathogenic.