ClinVar Genomic variation as it relates to human health

Variant summary: The ABCC8 c.221G>A (p.Arg74Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found at a low frequency in the control population (1/121894 control chromosomes). The variant was reported in the literature in multiple patients with congenital hyperinsulinemia (CHI) both in the homozgous and compound heterozygous states. Taken together, this variant is classified as pathogenic.

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with congenital hyperinsulinism. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Computational tools predict that this variant is damaging.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33046911, 30352420, 9618169, 27810688, 23275527, 20685672, 21992908, 23345197)

The p.Arg74Gln variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 9618169, 10338089, 10828824, 20685672, 23275527, 23345197, 28701683, 30352420, 36239000), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559734). 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: 495834) and has been interpreted as pathogenic by multiple sources. Of the many affected individuals, at least 5 were compound heterozygotes that carried a reported pathogenic variant in trans, and at least 1 was a homozygote, which increases the likelihood that the p.Arg74Gln variant is pathogenic (Variation ID: 9088, 188915, 210074, 188931; PMID: 23275527, 23345197, 30352420, 36239000). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PM2_supporting, PP3 (Richards 2015).

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 74 of the ABCC8 protein (p.Arg74Gln). This variant is present in population databases (rs72559734, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive familial hyperinsulinism (PMID: 21992908, 23345197). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 495834). 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 80%. This variant disrupts the p.Arg74 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14692646, 16429405, 24645945, 25518065). 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.

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