Submissions for variant NM_000352.6(ABCC8):c.4516G>A (p.Glu1506Lys)

dbSNP: rs137852671

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000201911	SCV000840601	pathogenic	not provided	2018-01-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009665	SCV001428462	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-04-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000201911	SCV003929855	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significantly lower ABCC8 protein levels in homozygous E1506K islets cells compared to wildtype, and homozygous mice exhibited enhanced insulin secretion and lower fasting blood glucose initially, but reduced insulin secretion and impaired glucose tolerance later in life (Shimomura et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16380471, 20573158, 18596924, 18390792, 21617188, 12559865, 23266803, 25926814, 26504125, 12627323, 26246406, 29739729, 11018078, 20042013, 23903354, 32928245)
OMIM	RCV000009665	SCV000029883	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2008-08-01	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000201911	SCV000256805	pathogenic	not provided	2015-10-07	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000009665	SCV002070462	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2020-10-08	no assertion criteria provided	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4516G>A, in exon 37 that results in an amino acid change, p.Glu1506Lys. The p.Glu1506Lys change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. This sequence change is absent from the large population databases (ExAC and gnomAD). The p.Glu1506Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This pathogenic sequence change has previously been described in the heterozygous state multiple families with hyperinsulinism, including in seven individuals from the same family with ABCC8-related hyperinsulinism (PMID: 11018078). In this family, the variant was maternally inherited in all cases. Out of the six transmitting females, two had a history of neonatal hypoglycemia and six had a history of permanent or gestational diabetes, suggesting that the p.Glu1506Lys variant is a dominantly inherited variant that is associated with hyperinsulinism in infancy and increased risk of insulin deficiency later in life (PMID: 11018078). All patients described in this publication were reported to have mild diazoxide responsive form of hyperinsulinism. The p.Glu1506Lys variant was also reported occurring in the de novo state in another family with persistent hypoglycemia in the newborn period and diabetes in adulthood (PMID: 20042013), and has been reported in the compound heterozygous state with a second ABCC8 variant in a patient with diazoxide unresponsive hyperinsulinism (PMID: 23266803). These collective evidences indicate that this sequence change is pathogenic.