ABCC8

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

ABCC8 was first reported in relation to autosomal dominant pulmonary arterial hypertension in 2018 (Bohnen et al., PMID:30354297). In total, twenty one variants (18 missense, 2 frameshift, and 1 splice-site) that have been reported and scored in twenty two probands in 4 publications (PMIDs:30354297, 35811711, 32934261 and 31727138) are included in this curation. Further cases were not scored due to diagnoses outside the scope of the PH GCEP (i.e. heritable and idiopathic PAH, not PAH associated with other diseases) (PMIDs:32934261, 31727138) or an allele frequency greater than 0.0001 (PMID: 33187088). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression studies. Bohnen et al. showed that ABCC8 mRNA was regularly expressed in the lungs of both PH patient cells and controls. Additionally, Bohnen et al. showed the presence of ABCC8 protein in proximal pulmonary arteries and alveolar macrophages (PMID:30354297). In summary, ABCC8 is moderately associated with autosomal dominant PAH. Evidence from both clinical observations and laboratory research has contributed to this gene-disease relationship receiving a “moderate” classification. In the future, additional reports of PAH patients with ABCC8 variants, experiments showing biochemical function, and model organisms demonstrating the PAH phenotypes could help strengthen the relationship between ABCC8 and PAH. This classification was approved by the ClinGen Pulmonary Hypertension Gene Curation Expert Panel on the meeting date 09/06/2021 (SOP Version 8) and revised on 8/30/2022 (SOP Version 9). The classification was re-evaluated on 11//12/2024 and 02/12/2025. Fourteen missense variants were re-scored as 0 points due to an allele frequency in gnomAD v2.1.1 control populations >0.0001 (i.e. exceeding the PH GCEP specified threshold for pathogenicity), or two out of three PH GCEP adapted in silico pathogenicity predictor scores not meeting pathogenicity thresholds (i.e. REVEL ≥0.75, CADD >20, AlphaMissense ≥ 0.564). In addition, one new null variant (PMID: 35811711) was added (1.5 points). The original classification of “moderate” did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0009734

Submitter: ClinGen

Inactivating variants in *ABCC8*, encoding the SUR1 (Sulfonylurea Receptor 1) regulatory subunit of the pancreatic beta-cell KATP channel, were first reported in relation to autosomal recessive congenital hyperinsulinism, in 1995 (Thomas et al., PMID: 7716548). Subsequently, autosomal dominant (Huopio et al., PMID:11018078; Thornton et al., PMID: 12941782) inheritance patterns have been reported for *ABCC8* -related hyperinsulinism. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern as well as mechanism and phenotypic variability among variants associated with recessive and dominant *ABCC8*-related hyperinsulinism, and monogenic diabetes. Therefore, the curation of *ABCC8 *has been split into (1) autosomal recessive and (2) autosomal dominant forms of hyperinsulinism (MONDO:0002177), and (3) monogenic diabetes (MONDO:0015967). *ABCC8*-related hyperinsulinism can be classified according to the pancreatic histopathology which is determined in part by the source of inheritance of the *ABCC8* variant. Diffuse pancreatic disease, characterized by increased numbers of islet cells with nucleomegaly throughout the pancreas, is caused by bi-allelic recessive loss-of-function or dominant missense/in-frame deletion *ABCC8* variants. Recessive variants, including stop gain, splice site, frame shift, missense and copy number variants, lead to absent, nonfunctional or less functional KATP channels. This results in persistent beta-cell membrane depolarization, calcium influx, and inappropriate insulin release, regardless of blood glucose levels. A range in disease-severity and treatment response is observed among children with recessive biallelic variants with those at the mildest end of the clinical spectrum having transient hyperinsulinism which responds well to treatment while others may have treatment-refractory disease that may require subtotal pancreatectomy to manage hypoglycemia. At least 300 different variants in the *ABCC8* gene including nonsense, splice site, frameshift, and missense variants have been reported in association with autosomal recessive hyperinsulinism in humans. Variants in this gene have been curated in at least 8 probands in 7 publications (PMIDs: 35621279, 23266803, 17466004, 24661758, 36034573, 26162674, 29739729), with clinical presentations consistent with *ABCC8*-related hyperinsulinism. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. Focal hyperinsulinism, typically characterized by a small lesion of endocrine cells, within an otherwise histologically unremarkable pancreas, is caused by a single paternally-inherited recessive inactivating variant followed by a somatic loss of the maternal chromosome 11p.15 region because of paternal uniparental isodisomy. The focal lesion develops because the chromosome 11p15.5 region contains several imprinted genes including the maternally-expressed H19 (a candidate tumor suppressor gene) and CDKN1C (a negative regulator of cell proliferation) and paternally-expressed growth factor genes such as IGF2. When paternal uniparental isodisomy occurs within a pancreatic beta-cell during fetal development, the imbalance between imprinted genes (increased IGF2 and diminished H19 and CDKN1C) gives rise to the increase in proliferation of a population of beta-cells resulting in the focal lesion. As this cell contains a heterozygous ABCC8 recessive variant on the paternal allele, the uniparental disomy unmasks the variant causing it to be homozygous which results in dysregulated insulin secretion from the focal lesion. Rapid parental testing should be performed for all individuals with a single heterozygous recessive *ABCC8* variant as paternal inheritance offers a positive predictive value up to 94% for focal HI (pubmed: 23275527 and 24401662). For these individuals pancreatic imaging using 18F-DOPA PET scan is recommended to confirm focal disease and localize the lesion prior to lesionectomy which is curative in >97% of cases. For these cases consultation with an HI expert is recommended. This gene–disease relationship is supported by functional assays, expression studies, and animal models. Homozygous K499X zebrafish (SUR1⁻/⁻) displayed a loss of KATP channel activity (PMID: 36455737). Furthermore, an in vitro human stem cell model with biallelic *ABCC8* knockout (*ABCC8*⁻/⁻) effectively recapitulated the phenotype of congenital hyperinsulinism, further supporting the pathogenicity of biallelic *ABCC8* loss-of-function variants (PMID: 28600547). Total points for the experimental evidence are 5.5. Total points for genetic and experimental evidence together are 17.5. In summary, *ABCC8* is definitively associated with autosomal recessive hyperinsulinism, with most cases presenting in early infancy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes GCEP on the meeting date January 7, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0017182

Submitter: Myriad Women's Health

Inheritance Pattern: AD

Disease ID:MONDO:0017184

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009734

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0020525

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0009734

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0030088

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012480

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: SD

Disease ID:MONDO:0009734

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009734

Submitter: Natera

Inheritance Pattern: SD

Disease ID:MONDO:0015967

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0009415

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0030088

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0030088

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0007455

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0100164

Submitter: Genomics England PanelApp

Inheritance Pattern: Unknown

Disease ID:MONDO:0012480

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0009415

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0020525

Submitter: Genomics England PanelApp

Inheritance Pattern: SD

Disease ID:MONDO:0015967

Submitter: ClinGen

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.

Inheritance Pattern: SD

Disease ID:MONDO:0009734

Submitter: Ambry Genetics

Inheritance Pattern: SD

Disease ID:MONDO:0030088

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0009734

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0017187

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0100164

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0009734

Submitter: Illumina

Inheritance Pattern: SD

Disease ID:MONDO:0005015

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009734

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0009734

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019207

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019333

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0005148

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: SD

Disease ID:MONDO:0016391

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0009415

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0002177

Submitter: ClinGen

Variants in the *ABCC8* gene, which encodes the SUR1(Sulfonylurea Receptor 1) regulatory subunit of the pancreatic beta- cell KATP channel, were first reported in relation to congenital hyperinsulinism in 1995 (Thomas et al., PMID: 7716548), with an autosomal recessive inheritance pattern. Heterozygous variants causing autosomal dominant hyperinsulinism presenting in infancy or early childhood, followed by later development of impaired glucose tolerance or diabetes, were first described in in 2000 (Huopio et al., PMID: 11018078). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern as well as mechanism and phenotypic variability among variants associated with dominant and recessive *ABCC8*-related hyperinsulinism, and monogenic diabetes. Therefore, the curation of *ABCC8* has been split into (1) autosomal dominant and (2) autosomal recessive forms of hyperinsulinism (MONDO:0002177), and (3) monogenic diabetes (MONDO:0015967). We note here that included in the autosomal recessive curation are paternally inherited monoallelic loss of function variants that result in focal hyperinsulinsm due to somatic loss of the maternal chromosome 11p15 region due to somatic uniparental disomy, because ultimately they are recessively acting.     The clinical presentation among individuals with dominant heterozygous variants is variable, often presenting as a milder form of congenital hyperinsulinism (CHI) in infancy than the recessive form, with subtle or intermittent hypoglycemia that responds well to medical therapy. Others experience severe, treatment-refractory hypoglycemia that may require subtotal pancreatectomy.   In some cases, the hypoglycemia is not severe enough to be detected during infancy, and thus may go unrecognized or misdiagnosed until adolescence or adulthood when they may develop mild hypoglycemia or, paradoxically, impaired glucose tolerance or diabetes. Heterozygous dominant *ABCC8* variants cause diffuse pancreatic histology. In rare cases, atypical histological findings, characterized by features consistent with diffuse disease confined to localized regions of the pancreas, have been linked to somatic mosaicism for a dominant *ABCC8* variant. All reported dominant *ABCC8* variants have been missense changes or in-frame deletion variants associated with this broad spectrum of clinical severity in hyperinsulinism (PMIDs: 20573158, 11018078, 31218401, 22106158, 18596924, 31464105). The mechanism for many dominantly acting variants appears to be the generation of a SUR1 subunit that can participate in the formation of a KATP channel heterooctamer (which normally consists of four SUR1 subunits and four Kir6.2 [encoded by *KCNJ11*] subunits) that can localize to the cell membrane but has a diminished response to MgADP (PMID: 18596924). Because of the existence of some normal or partially normal KATP channels, individuals with dominant variants are more likely to respond to treatment with diazoxide (PMIDs: 18596924, 31464105) than those with the recessive form (PMID: 23275527). Dominantly acting variants in this gene have been curated in at least 16 probands in 9 publications (PMIDs: 39441403, 20573158, 11018078, 31218401, 20042013, 22106158, 18596924, 21536946, 31464105) with clinical presentations consistent with ABCC8-related hyperinsulinism. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene–disease relationship is strongly supported by functional studies, expression data, and animal models. Total points for the experimental evidence are 3. Total points for genetic and experimental evidence together are 15.  In summary,  *ABCC8* is definitively associated with autosomal dominant hyperinsulinism, with most cases presenting in early infancy or childhood. Some cases have a mild presentation that is missed in infancy but may be noticed in later childhood or adulthood manifesting as mild hypoglycemia or impaired glucose tolerance or diabetes. This classification was approved by the ClinGen Monogenic Diabetes GCEP on the meeting date January 7, 2026 (SOP Version 11).