ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1493 of the ABCC8 protein (p.Arg1493Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with congenital autosomal recessive hyperinsulinism (PMID: 10426386, 12199344, 21968111, 25008049). This variant is also known as R1494Q. ClinVar contains an entry for this variant (Variation ID: 370910). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg1493 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9769320, 15579781, 30186238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Identified in multiple other unrelated patients with hyperinsulinism in the published literature, often inherited on the paternal allele; somatic 11p maternal allele studies were not performed (Sang et al., 2014; Gong et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Occasionally reported as R1494Q using alternate nomenclature; This variant is associated with the following publications: (PMID: 14692646, 23275527, 21968111, 12199344, 20799350, 23226049, 20685672, 25639667, 10426386, 25008049)

The p.Arg1493Gln variant in ABCC8 has been reported in 8 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 12199344, 25639667, 21968111, 34304300, 25008049, 23275527, 10426386), and has been identified in 0.0008% (1/129096) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746480424). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 370910) and has been interpreted as pathogenic by Invitae and likely pathogenic by Counsyl and GeneDx. Of the 8 affected individuals, at least 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg1493Gln variant is pathogenic (PMID: 10426386, 25008049). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg1493Trp has been reported in association with disease in ClinVar and the literature, supporting that a change at this position may not be tolerated (Variation ID: 9096, PMID: 30186238, 33688939, 10202168, 10426386, 19475716, 9769320, 15579781). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PM5, PP3, PP2_supporting (Richards 2015).