ClinVar Genomic variation as it relates to human health

NM_000352.3(ABCC8):c.4198G>A(G1400R) is a missense variant classified as likely pathogenic in the context of ABCC8-related hyperinsulinism. G1400R has been observed in cases with relevant disease (PMID: 31464105, 23275527, 17378627, 19475716, 17919176, 30114684). Functional assessments of this variant are available in the literature (PMID: 22802590, 31464105). G1400R has been observed in population frequency databases (gnomAD: NFE 0%). In summary, NM_000352.3(ABCC8):c.4198G>A(G1400R) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The p.Gly1400Arg variant in ABCC8 has been reported in at least 6 individuals with hyperinsulinemic hypoglycemia (PMID: 16357843, 17378627, 19475716, 23275527, 30114684, 31464105), and has been identified in 0.004% (4/98246) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852676). 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. Of the 6 affected individuals, at least 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly1400Arg variant is pathogenic (Variation ID: 553929; PMID: 16357843, 19475716). In vitro functional studies provide some evidence that the p.Gly1400Arg variant may slightly impact protein function (PMID: 31464105, 22802590). 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_strong, PP3, PM2_supporting, PS3_supporting (Richards 2015).

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1400 of the ABCC8 protein (p.Gly1400Arg). This variant also falls at the last nucleotide of exon 34, which is part of the consensus splice site for this exon. This variant is present in population databases (rs137852676, gnomAD 0.001%). This missense change has been observed in individual(s) with autosomal recessive neonatal diabetes and congenital hyperinsulinism (PMID: 17668386, 19475716). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Gly1401Arg. ClinVar contains an entry for this variant (Variation ID: 35616). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 22802590, 31464105). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Variant summary: ABCC8 c.4198G>A (p.Gly1400Arg) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 195184 control chromosomes. c.4198G>A has been reported in the literature as a heterozygous and compound heterozygous genotype in individuals affected with focal and diffuse forms of Congenital Hyperinsulinism (example, Stanley_2004, Suchi_2006, Greer_2007, Ellard_2007, Rafiq_2008, Sandal_2009, Dastamani_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.