PROC was first reported in relation to semidominant hereditary thrombophilia due to congenital protein C deficiency in 1987 (Romeo G, et al., 1987, PMID: 2437584). Over 400 unique variants (primarily missense, but also nonsense, splicing, frameshifts, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 20 probands in 5 publications (PMIDs: 2437584, 25393254, 11380450, 25618265, and 21621249). Variants in this gene segregated with disease in 14 additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease relationship is supported by its biochemical function in factor V and VIII inactivation (PMID: 6791548), its interaction with protein S (PMID: 28514442) and both deficient and null mouse models which recapitulate phenotypes observed in humans (PMID: 15902301, PMID: 9788960). In summary, PROC is definitively associated with semidominant hereditary thrombophilia due to congenital protein C deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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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