GGCX was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2019 (Zhu et al., PMID: 31727138). 14 variants (9 missense, 4 nonsense, 1 frameshift) reported in 18 probands in 1 publication (PMID:31727138) were included in this curation. The 18 probands were identified using exome sequencing as part of a large cohort (n = 2572 participants) from the National Biological Sample and Data Repository for PAH. The mechanism of pathogenicity was unclear.
This gene-disease relationship is also supported by expression evidence (PMID: 23715323). GTEx analysis revealed normal expression in human lung and liver tissue, which is consistent with the PAH phenotype.
In summary, the evidence supporting a gene-disease relationship between GGCX and autosomal dominant PAH was moderate. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on the meeting date 8/30/2022 (SOP Version 9).
The classification was re-evaluated on January 8th, 2025 and May 14th, 2025. As a result of re-evaluation, two missense variants were re-scored as 0 (-0.2) points due to conflicting in silico pathogenicity predictions (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). Although a new I/HPAH patient cohort (N=45) from central Taiwan was reported (PMID: 35811711), the variants identified did not pass the PH GCEP pathogenicity threshold for inclusion. 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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