ClinVar Miner

Submissions for variant NM_004975.4(KCNB1):c.575C>T (p.Ala192Val)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV004405977 SCV004889013 uncertain significance Inborn genetic diseases 2023-10-11 criteria provided, single submitter clinical testing The c.575C>T (p.A192V) alteration is located in exon 2 (coding exon 2) of the KCNB1 gene. This alteration results from a C to T substitution at nucleotide position 575, causing the alanine (A) at amino acid position 192 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV005065052 SCV005698018 uncertain significance Developmental and epileptic encephalopathy, 26 2024-05-13 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 192 of the KCNB1 protein (p.Ala192Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with KCNB1-related conditions. 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 80%. This variant disrupts the p.Ala192 amino acid residue in KCNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 36257979). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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