ClinVar Genomic variation as it relates to human health

The c.928G>A;p.(Asp310Asn) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 585352; PMID: 27908292; 27188453; 23275527; 21536946; 20427569; 18596924) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 20427569) - PS3_supporting. The variant is present at low allele frequencies population databases (rs769569410– gnomAD 0.00006569%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic

The p.Asp310Asn variant in ABCC8 has been previously reported in 3 individuals with hyperinsulinemic hypoglycemia (PMID: 16429405, 17236890, 27908292) and has been seen in 0.006% (2/34590) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs769569410). 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: 585352) and has been interpreted as likely pathogenic by Fulgent Genetics, DASA, Natera Inc, Athena Diagnostics Inc, and Invitae. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans, which increases the likelihood that the p.Asp310Asn variant is pathogenic (PMID: 17236890). In vitro functional studies provide some evidence that the p.Asp310Asn variant may slightly impact protein function (PMID: 18596924, 20427569). However, these types of assays may not accurately represent biological function. 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, 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, PP3, PM2, PS3_supporting (Richards 2015).

Variant summary: ABCC8 c.928G>A (p.Asp310Asn) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250942 control chromosomes (gnomAD). c.928G>A has been reported in the literature in individuals affected with Familial Hyperinsulinism (Fernandez-Marmiesse2006, Pinney_2008, Martnez_2016, Salomon-Estebanez_2016, Motte-Signoret_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports this variant affects protein function (Pinney_JCI_2008). The following publications have been ascertained in the context of this evaluation (PMID: 31464105, 16429405, 21536946, 27188453, 36144251, 18596924, 27908292, 23275527). ClinVar contains an entry for this variant (Variation ID: 585352). Based on the evidence outlined above, the variant was classified as likely pathogenic.

PM2_Supporting+PP3_Moderate+PS4_Moderate+PP4

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 310 of the ABCC8 protein (p.Asp310Asn). This variant is present in population databases (rs769569410, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital hyperinsulinism and type 2 diabetes (PMID: 16429405, 18596924, 27188453, 33046911). ClinVar contains an entry for this variant (Variation ID: 585352). 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%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18596924, 20427569). This variant disrupts the p.Asp310 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 17236890; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.

The ABCC8 c.928G>A variant is predicted to result in the amino acid substitution p.Asp310Asn. This variant has been reported in the heterozygous and compound heterozygous states in multiple individuals with congenital hyperinsulinism (see for example, Table 1, Fernandez-Marmiesse et al. 2006. PubMed ID: 16429405; Table 2, Martínez et al. 2016. PubMed ID: 27188453; Motte-Signoret et al. 2022. PubMed ID: 36144251). Functional studies have shown that this variant affects ABCC8 surface expression and function (Table 4, Pinney et al. 2008. PubMed ID: 18596924; Figure 5, Yan et al. 2010. PubMed ID: 20427569). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. An alternative substitution affecting the same amino acid (p.Asp310Val) has been reported in association with hyperinsulinism (Table 2, Hardy et al. 2007. PubMed ID: 17236890). This variant is interpreted as pathogenic.