Submissions for variant NM_000352.6(ABCC8):c.3440T>G (p.Leu1147Arg)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003322263	SCV004026524	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Leu1147Arg variant in ABCC8 has been reported in at least 2 individuals with hyperinsulinemic hypoglycemia (PMID: 16429405, 18339976, DOI: 10.3266/RevEspEndocrinolPediatr.pre2018.Jun.420), and has been identified in 0.006% (2/34432) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1262517518). 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 at least 2 affected individuals, both were compound heterozygotes that carried reported pathogenic variants in trans, which increases the likelihood that the p.Leu1147Arg variant is pathogenic (Variation ID: 217846, 370163; PMID: 16429405, 18339976, DOI: 10.3266/RevEspEndocrinolPediatr.pre2018.Jun.420). 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 (Richards 2015).
Baylor Genetics	RCV003466060	SCV004192904	likely pathogenic	Type 2 diabetes mellitus	2023-10-28	criteria provided, single submitter	clinical testing
GeneDx	RCV004719319	SCV005325036	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a patient with features of MODY in published literature (PMID: 31595705); 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: 37216904, 34014594, 31595705, 25306193, 34631896, 18339976)
Labcorp Genetics (formerly Invitae), Labcorp	RCV004719319	SCV005835831	uncertain significance	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1147 of the ABCC8 protein (p.Leu1147Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of ABCC8-related disorders (PMID: 25306193). ClinVar contains an entry for this variant (Variation ID: 2576202). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCC8 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004736333	SCV005362788	uncertain significance	ABCC8-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The ABCC8 c.3440T>G variant is predicted to result in the amino acid substitution p.Leu1147Arg. This variant (also described as c.3443T>G, p.Leu1148Arg in NM_001287174) has been reported in the heterozygous and compound heterozygous states in multiple individuals with hyperinsulinemic hypoglycemia (Gussinyer et al. 2008. PubMed ID: 18339976; Snider et al. 2013. PubMed ID: 23275527; Alkorta-Aranburu et al. 2014. PubMed ID: 25306193; Arango et al. 2018. DOI:10.3266/RevEspEndocrinolPediatr.pre2018.Jun.420). However, one patient with a hyperinsulinemic state at birth, only presented with glucose intolerance at age 24 (Patient 3 in Gussinyer et al. 2008. PubMed ID: 18339976). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence.