Submissions for variant NM_000352.6(ABCC8):c.76T>A (p.Cys26Ser)

gnomAD frequency: 0.00001  dbSNP: rs1462559571

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001817862	SCV002067268	pathogenic	not provided	2019-02-26	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.76T>A, in exon 1 that results in an amino acid change, p.Cys26Ser. This pathogenic sequence change has previously been described in the compound heterozygous state a patient with ABCC8-related hyperinsulinemic hypoglycemia (PMID: 21199866). Fukada et al. found that the p.Cys26 position is high conserved in ABC transporters due to Cys-Cys bonds that occur within these transporter proteins. In vitro analysis of the p.Cys26Ser change showed that it affected SUR1 maturation (i.e. full glycosylation) by interfering with the formation of a Cys-Cys bond between p.Cys6 and p.Cys26 (PMID: 21199866). The p.Cys26Ser change affects a highly conserved amino acid residue located in a domain of the SUR1 protein that is known to be functional. The p.Cys26Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL)." DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.76T>A, in exon 1 that results in an amino acid change, p.Cys26Ser. This pathogenic sequence change has previously been described in the compound heterozygous state a patient with ABCC8-related hyperinsulinemic hypoglycemia (PMID: 21199866). Fukada et al. found that the p.Cys26 position is high conserved in ABC transporters due to Cys-Cys bonds that occur within these transporter proteins. In vitro analysis of the p.Cys26Ser change showed that it affected SUR1 maturation (i.e. full glycosylation) by interfering with the formation of a Cys-Cys bond between p.Cys6 and p.Cys26 (PMID: 21199866). The p.Cys26Ser change affects a highly conserved amino acid residue located in a domain of the SUR1 protein that is known to be functional. The p.Cys26Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844417	SCV002103457	likely pathogenic	Familial hyperinsulinism	2024-06-03	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.76T>A (p.Cys26Ser) results in a non-conservative amino acid change in 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 4.1e-06 in 244362 control chromosomes. c.76T>A has been reported in the literature in at least one individual affected with hyperinsulinemic hypoglycemia (Fukuda_2011). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function and showed that C26S led to instability and ER retention (Fukuda_2011, Wang_2012). The following publications have been ascertained in the context of this evaluation (PMID: 21199866, 22311976). ClinVar contains an entry for this variant (Variation ID: 1338491). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003321875	SCV004026589	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Cys26Ser variant in ABCC8 was observed in two individuals with hyperinsulinemic hypoglycemia (PMID 21199866, unpublished data), and has been identified in 0.0009% (1/109276) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1462559571). 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: 1338491) and has been interpreted as pathogenic by the Genetics Services Laboratory (University of Chicago) and likely pathogenic by the Women's Health and Genetics Laboratory (LabCorp). Of the 2 affected individuals, 1 of those were homozygote, which increases the likelihood that the p.Cys26Ser variant is pathogenic (unpublished data). In vitro functional studies provide some evidence that the p.Cys26Ser variant impacts protein trafficking to the cell surface in COSm6 and HEK293 cells (PMID: 21199866, 22311976). 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, (p.Cys26Trp), has been reported in association with disease (unpublished data), supporting that a change at this position may not be tolerated. 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: PS3_supporting, PM2_supporting, PP3, PM5, PM3_supporting (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV005040403	SCV005676127	likely pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-06-03	criteria provided, single submitter	clinical testing