ClinVar Miner

Submissions for variant NM_004975.4(KCNB1):c.1136G>T (p.Gly379Val)

dbSNP: rs1984249721
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001333329 SCV001525880 pathogenic Developmental and epileptic encephalopathy, 26 2018-11-19 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This c.1136G>T (p.G379V) variant has been previously reported to occur de novo in one individual with developmental delay, regression, and seizures [PMID 28173649] An allelic variant affecting the same amino acid, c.1135G>A (p.G379R) has also been reported in two patients with seizures or atypical Rett syndrome [PMID 25164438, 29322350] Functional assay using the mutant protein showed a loss of ion selectivity and gain of a depolarizing inward cation conductance [PMID 25164438] Of note, variant affecting a neighboring amino acid p.V378L was seen in one patient with non-syndromic intellectual disability without epilepsy [PMID: 27928161].
Labcorp Genetics (formerly Invitae), Labcorp RCV001333329 SCV004298097 pathogenic Developmental and epileptic encephalopathy, 26 2024-05-15 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 379 of the KCNB1 protein (p.Gly379Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 28173649, 35071126). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1031489). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNB1 function (PMID: 35071126). For these reasons, this variant has been classified as Pathogenic.

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