Submissions for variant NM_000352.6(ABCC8):c.331G>A (p.Gly111Arg)

gnomAD frequency: 0.00001  dbSNP: rs761749884

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193936	SCV000246294	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2015-06-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000193936	SCV000486456	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2016-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068772	SCV001233904	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 111 of the ABCC8 protein (p.Gly111Arg). This variant is present in population databases (rs761749884, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 20943781, 21992908, 23345197, 23652837, 25117148, 25201519, 30352420). ClinVar contains an entry for this variant (Variation ID: 210074). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 15579781, 27573238). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804929	SCV002051106	pathogenic	Familial hyperinsulinism	2021-12-14	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.331G>A (p.Gly111Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251372 control chromosomes. c.331G>A has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism (Kapoor_2013, Wang_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 pathogenic.
Molecular Genetics, Madras Diabetes Research Foundation	RCV000193936	SCV002318429	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000193936	SCV004026583	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Gly111Arg variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 15579781, 15466080, 20943781, 23652837, 23345197, 25117148, 25201519, 25972930), and has been identified in 0.003% (1/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761749884). 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: 210074) and has been interpreted as pathogenic by Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Genetic Services Laboratory (University of Chicago) and as likely pathogenic by Counsyl and Molecular Genetics (Madras Diabetes Research Foundation). Of the many affected individuals, at least 3 were compound heterozygotes that carried a reported pathogenic variant in trans, and at least 2 were homozygotes, which increases the likelihood that the p.Gly111Arg variant is pathogenic (Variation ID: 551999; PMID: 23652837, 15466080, 23345197, 15579781, 20943781). In vitro functional studies provide some evidence that the p.Gly111Arg variant may slightly impact protein function (PMID: 15579781). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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, PS3_supporting (Richards 2015).
Neuberg Centre For Genomic Medicine, NCGM	RCV000193936	SCV004100576	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468881	SCV004191760	pathogenic	Type 2 diabetes mellitus	2023-09-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042410	SCV005676113	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-01-20	criteria provided, single submitter	clinical testing