Submission Details

ATP-binding cassette subfamily C, member 6 (ABCC6) was first reported in relation to autosomal dominant/autosomal recessive pseudoxanthoma elasticum (PXE) in 2000 by three research groups (Ringpfeil et al., PMID 10811882; Bergen et al., PMID 10835643; Le Saux et al., PMID 10835642). Pseudoxanthoma elasticum is characterized by calcifications that manifest subcutaneously in yellow papules, in the eyes as angioid streaks or in arterial walls. A more severe presentation of disease was first reported in 2012 as autosomal recessive generalized arterial calcification of infancy (GACI) which had previously only been linked to biallelic variation in ENPP1 (Nitschke et al., PMID 22200248). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity, pseudoxanthoma elasticum (AR; OMIM:264800), generalized arterial calcification of infancy 2 (AR; OMIM:614473) and forme fruste pseudoxanthoma elasticum (AD; OMIM:177850). The association of monoallelic ABCC6 variation and PXE is debated in the literature, however, heterozygous variant carriers have been documented with clinical and/or histopathological indications of PXE as well as a potential for increased cardiovascular calcification or stroke (PMIDs 40725385, 29722917). 18 variants (3 nonsense, 6 missense, 6 frameshift, 2 splice-site, 1 multi-exon deletion) that have been reported in 17 probands in 4 publications (PMIDs: 10811882, 10835643, 22209248, 29709427) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, rescue in a mouse model, and biochemical evidence (PMIDs: 16135817, 36769695, 28416300). Biallelic knockout of ABCC6 in mouse models recapitulates the calcification phenotype seen in humans as well as the reduction in circulating inorganic pyrophosphate (ppi) which has been reported as an inhibitor of calcification. It was also shown that while there is a significant reduction in ppi between controls and PXE patients, there was not a connection between the severity of phenotypes and the measured ppi levels. In summary, there is definitive evidence supporting the relationship between ABCC6 and semidominant ABCC6-related generalized arterial calcification. 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 Neurovascular Disease GCEP on the meeting date October 22, 2025 (SOP Version 11).