Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV001817837 | SCV002069303 | likely pathogenic | not provided | 2020-02-03 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the KCNJ11 gene demonstrated a sequence change, c.556C>G, in exon 1 that results in an amino acid change, p.His186Asp. This sequence change has not been observed in large population databases (ExAC, gnomAD). The p.His186Asp change affects a highly conserved amino acid residue located in a domain of the KCNJ11 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His186Asp substitution. This particular amino acid change has been described in the literature in other patients with permanent neonatal diabetes who were successfully treated with oral sulfonylureas (PMIDs: 26388896, 29205704). |
Invitae | RCV001817837 | SCV002292066 | pathogenic | not provided | 2023-11-03 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 186 of the KCNJ11 protein (p.His186Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant neonatal diabetes mellitus (PMID: 24622368, 26388896; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1338466). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |