Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Kasturba Medical College, |
RCV001376163 | SCV001573214 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | criteria provided, single submitter | clinical testing | ||
Genetic Services Laboratory, |
RCV001820080 | SCV002069036 | pathogenic | not provided | 2021-10-04 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4369G>A, in exon 36 that results in an amino acid change, p.Ala1457Thr. This sequence changed has not been described in the population databases such as ExAC and gnomAD (dbSNP rs72559717). The p.Ala1457Thr change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Ala1457Thr sequence change has previously been described in the heterozygous state in a patient with ABCC8-related hyperinsulinism, inherited from the patient's unaffected father (PMID: 21536946). This sequence change has also been reported in the compound heterozygous state with a second ABCC8 sequence change in a patient with severe diazoxide unresponsive hyperinsulinism (PMID: 12627323). Functional studies provided evidence to suggest that this variant impairs normal function of the ABCC8 (SUR1) protein (PMID: 21536946). This sequence change has been reported in multiple patients who showed responsiveness to diazoxide and inherited the variant in an autosomal dominant manner (PMID: 31464105). Thus, the p.Ala1457Thr pathogenic sequence change may function in an autosomal dominant manner with reduced penetrance, and may also be associated with autosomal recessive disease. |
Labcorp Genetics |
RCV001820080 | SCV004295371 | pathogenic | not provided | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1457 of the ABCC8 protein (p.Ala1457Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism and/or autosomal dominant early onset diabetes (PMID: 21536946, 27538677, 31464105). In at least one individual the variant was observed to be de novo. This variant is also known as A1458T. ClinVar contains an entry for this variant (Variation ID: 1065615). 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 ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 12627323, 21536946, 31464105). For these reasons, this variant has been classified as Pathogenic. |