Submission Details

Activating variants in ABCC8, encoding the SUR1 regulatory subunit of the pancreatic beta cell KATP channel, were first reported in relation to autosomal dominant monogenic diabetes, specifically in a neonatal diabetes cohort, in 2006 (Babenko et al., PMID: 16885549). It is important to note that inactivating (loss of function) variants in ABCC8 cause hyperinsulinemic hypoglycemia. Isolated heterozygosity for an inactivating variant in ABCC8 is not a cause of monogenic diabetes. It is thus especially crucial to have phenotypic information when evaluating the pathogenicity of ABCC8 variants.

We have curated the inheritance pattern for ABCC8 monogenic diabetes as semidominant because while most cases are autosomal dominant, there have since been reported a few cases with a recessive mode of inheritance (Ellard et al, 2007, PMID: 17668386). The mechanism for dominant cases is activating variants resulting in a KATP channel unable to close in response to ATP, impairing insulin secretion. The occasional recessive cases are caused by either (1) homozygosity or compound heterozygosity for partially activating variants or (2) a partially activating variant that only causes diabetes when inherited in trans with an inactivating variant (PMID: 17668386). At least 40 diabetes-causing variants (primarily missense) have been reported in humans. Evidence supporting relationship of this gene with diabetes includes case-level data, segregation data, and experimental data. Summary of case-level and segregation data: 12 points. Variants in this gene have been reported in at least 43 probands in 6 publications (PMIDs: 21989597, 27538677, 31604004, 31562829, 16885549, 17668386, 32027066), with most cases presenting as either permanent or transient neonatal diabetes but a few presenting later in childhood or young adulthood, which could represent a missed transient neonatal diabetes diagnosis. Variants in this gene segregated with disease in 17 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by functional assays, expression studies, and animal models. In a Sur1 knockout mouse model, mice exhibited absence of KATP channels in pancreatic beta-cells, spontaneous electrical activity, and altered response to glucose stimulation (PMID: 10734066). The ABCC8 encoded protein, SUR1, has been reported to act as the regulatory subunit of the KATP channel and modulate ATP-sensitive potassium channels and therefore insulin release, with glucose increase causing increase in ATP levels which inhibits SUR1 and closes the KATP channel (PMID: 24768178). SUR1 and Kir6.2 were shown to physically interact through coimmunoprecipitation (PMID: 9488482), and ABCC8 expression has been confirmed in pancreatic tissue (PMID: 24309898). Total points for experimental evidence: 4. Total points for genetic and experimental evidence: 16.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the curation of ABCC8 has been split into multiple disease entities, which in addition to monogenic diabetes include hyperinsulinemic hypoglycemia (MONDO:0018619), susceptibility to type 2 diabetes (MONDO:0005148), and pulmonary hypertension (MONDO: 0005149). These will be curated separately. In summary, ABCC8 is definitively associated with semidominant monogenic diabetes, with most cases presenting in infancy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.