ClinVar Genomic variation as it relates to human health

Variant summary: ABCC8 c.3641G>A (p.Arg1214Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain 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 2e-05 in 246460 control chromosomes. c.3641G>A has been reported in the literature in multiple individuals affected with Neonatal Diabetes Mellitus, both as a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on ATP-sensitive potassium channel activity, which showed the variant results in <30% of normal activity (Shyng_1998). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1214 of the ABCC8 protein (p.Arg1214Gln). This variant is present in population databases (rs367850779, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 15562009, 20685672). This variant is also known as R1215Q. ClinVar contains an entry for this variant (Variation ID: 632619). 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: 9648840). This variant disrupts the p.Arg1214 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17575084, 23275527, 24401662, 24937539, 26180531). 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.

A compound heterozygous variation in exon 29 of the ABCCB gene that results in the amino acid substitution of Glutamine for Arginine at codon 1214 was detected. The observed variant c.3641G>A (p.Arg1214Gln) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

The p.Arg1214Gln variant in ABCC8 has been reported in at least 5 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 15562009, 9618169, 9648840, 14715863, 14692646), and has been identified in 0.005% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs367850779). 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: 632619) and has been interpreted as pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Kasturba Medical College (Manipal, Manipal Academy of Higher Education), Invitae, Foundation for Research in Genetics and Endocrinology (FRIGE's Institute of Human Genetics), Natera Inc., and Fulgent Genetics. Of the 5 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg1214Gln variant is pathogenic (Variation ID: 9088, 371380; PMID: 9648840, 14692646). In vitro functional studies provide some evidence that the p.Arg1214Gln variant may slightly impact protein function (PMID: 9648840). 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).