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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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