ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly40 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ11-related conditions (PMID: 16357843, 24401662, 28123437), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 10559219). 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 KCNJ11 protein function. ClinVar contains an entry for this variant (Variation ID: 551373). This missense change has been observed in individual(s) with paternally inherited focal hyperinsulinism (PMID: 16357843). This variant has been reported in individual(s) with autosomal dominant diffuse hyperinsulinism (PMID: 27908292); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 40 of the KCNJ11 protein (p.Gly40Asp).