Submission Details

GGCX was first reported in relation to autosomal recessive vitamin K-dependent clotting factors, combined deficiency of, type 1 (VKCFD1) in 1998 (Brenner B, et al., 1998, PMID: 9845520). VKCFD1 is a bleeding disorder characterized by the reduced activities of the procoagulant factors II, VII, IX, and X and anticoagulant proteins C and S. Additional bone, cardiac, skin, and ocular phenotypes are also present in patients. GGCX encodes vitamin K-dependent gamma-carboxylase which catalyzes the carboxylation of specific Glu residues in the intracellular precursors of certain proteins to gamma-carboxyglutamly (Gla) residues in mature proteins. Carboxylation of glutamic acid residues occurs in a number of proteins, including the procoagulants factors II, VII, IX, and X; the anticoagulants protein C and protein S. Carboxylation of other proteins such as osteocalcin and matrix Gla protein may explain additional phenotypes in bone, skin and eyes. For all disease phenotypes the mechanism of pathogenicity is reported to be partial loss of function (hypomorphic). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found overlapping phenotypes with no difference in molecular mechanism or inheritance pattern, therefore, the following disease entities have been lumped into one VKCFD1 disease entity; (OMIM: 277450) Vitamin K-dependent clotting factors, combined deficiency of, 1, and (OMIM: 610842) Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency. Of note a single publication has reported GGCX in relation to Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa (PMID: 24739904), this has not been considered within this curation. As reviewed in PMID: 28125048, at least 32 variants (variant type, e.g. missense, nonsense, frameshift, and splicing) have been reported and 18 variants from 13 probands in 8 publications (PMIDs: 9845520, 17110937, 16720838, 19116367, 26758921, 25151188, 15287948, 29175035) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by its biochemical function in carboxylation (PMID: 2617472), which is altered in patients (PMID: 19116367), its enriched expression in the liver (PMID: 9166845), and mouse models (PMIDs: 17327402, 24520408). In summary, GGCX is definitively associated with autosomal recessive VKCFD1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.