Submissions for variant NM_000312.4(PROC):c.565C>T (p.Arg189Trp)

gnomAD frequency: 0.00026  dbSNP: rs146922325

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148748	SCV000190485	uncertain significance	Thrombophilia due to protein C deficiency, autosomal dominant	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Illumina Laboratory Services, Illumina	RCV000148748	SCV000416364	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2017-04-27	criteria provided, single submitter	clinical testing	The PROC c.565C>T (p.Arg189Trp) variant is reported as a cause of type II protein C deficiency that produces a protein with decreased functional activity and a relatively normal antigen level. Heterozygous carriers of pathogenic variants in the PROC gene are said to have mild protein C deficiency which is often asymptomatic, but may involve recurrent venous thrombosis. Tang et al. (2012) identified the p.Arg189Trp variant in 17 of 36 individuals diagnosed with hereditary protein C deficiency. All 17 individuals were heterozygous for the variant, had repeated low plasma protein C activity, and a clinical history of deep vein thrombosis (DVT). The authors then evaluated the p.Arg189Trp variant in a case-control study and found the variant in 59 of 1003 individuals with venous thrombosis. The authors conclude that the p.Arg189Trp variant is the most frequent pathogenic variant associated with protein C deficiency in the Chinese population and a significant risk factor for venous thrombosis. The p.Arg189Trp variant has also been reported in more recent study in which it is found in one individual in a compound heterozygous state (Kim et al. 2014). The p.Arg189Trp variant is reported in a heterozygous state in nine out of 4031 controls and at a frequency of 0.01984 in the East Asian population of the Exome Aggregation Consortium including two homozygotes. This allele frequency is high but is consistent with the disease prevalence. Based on the evidence from the literature, the p.Arg189Trp variant is classified as pathogenic for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851825	SCV000899809	likely pathogenic	Reduced protein C activity	2019-02-01	criteria provided, single submitter	research
Mendelics	RCV000148748	SCV001135947	uncertain significance	Thrombophilia due to protein C deficiency, autosomal dominant	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000148748	SCV001411830	uncertain significance	Thrombophilia due to protein C deficiency, autosomal dominant	2022-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 189 of the PROC protein (p.Arg189Trp). This variant is present in population databases (rs146922325, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with venous thromboembolism and PROC-deficiency (PMID: 7482420, 22545135, 22817391, 22944127, 23332921, 24028705, 24162787, 28111891, 32717757). ClinVar contains an entry for this variant (Variation ID: 161342). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects PROC function (PMID: 23389250). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetics and Molecular Pathology, SA Pathology	RCV000148748	SCV002761626	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2019-12-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV002468568	SCV002764635	established risk allele	Thrombophilia 3 due to protein C deficiency		no assertion criteria provided	research	The PROC c.565C>T (p.Arg189Trp) (also known as the p.Arg147Trp variant in the literature) has been identified as a common variant causing protein C deficiency among East Asian populations, with a reported frequency of 27.8% in the protein C deficient Chinese population (Ding_2014_PMID:23389250). The variant has been identified in numerous homozygous and heterozygous individuals with deep vein thrombosis (DVT) and protein C deficiency (Duc Do_2021_PMID:32964666, Tang_2012_PMID:22545135, Li_2018_PMID:30210609, Ding_2014_PMID:23389250, Tang_2012_PMID:22817391). One case-control study in a Chinese DVT patient population identified the p.Arg189Trp variant at a frequency of 5.88% in the DVT population compared to 0.87% in healthy controls, and identified that first-degree relatives of affected patients who harbour the p.R189W variant have an 8.8-fold increased risk of venous thrombosis (Tang_2012_PMID:22817391, Tang_2012_PMID:22545135). The variant was identified in dbSNP (ID: rs146922325) and ClinVar (classified as uncertain by Invitae, Mendelics and 1 other submitter, pathogenic by Illumina, and likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 202 of 282736 chromosomes (2 homozygous) at a frequency of 0.0007144, and was observed at the highest frequency in the East Asian population in 156 of 19950 chromosomes (freq: 0.007820) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Arg189 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI) predict an uncertain effect on splicing. The p.Arg189Trp variant has shown to exhibit ~3 fold lower affinity for binding the EPCR transmembrane receptor (Ding_2014_PMID:23389250). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic – risk factor for thrombophilia due to protein C deficiency.