Submissions for variant NM_000312.4(PROC):c.631C>T (p.Arg211Trp)

gnomAD frequency: 0.00001  dbSNP: rs121918143

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000000693	SCV000190475	likely pathogenic	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000693	SCV000817071	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2024-05-15	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 211 of the PROC protein (p.Arg211Trp). This variant is present in population databases (rs121918143, gnomAD 0.02%). This missense change has been observed in individuals with purpura fulminans and severe protein C deficiency and venous thromboembolism and partial protein C deficiency (PMID: 3185623, 8165644, 10805275, 10942114, 18573519, 18954896, 24162787, 28111891). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg157Trp or Arg169Trp. ClinVar contains an entry for this variant (Variation ID: 659). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROC protein function. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851836	SCV000899837	likely pathogenic	Reduced protein C activity	2019-02-01	criteria provided, single submitter	research
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000000694	SCV004809565	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive	2024-04-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000693	SCV005399058	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with thrombophilia due to protein C deficiency, autosomal dominant (MIM#176860) and autosomal recessive (MIM#612304). (I) 0108 - This gene is associated with both recessive and dominant diseases (MIM#176860, MIM#612304). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Other missense variant comparable to the one identified in this case have limited previous evidence for pathogenicity. Changes to leucine and glutamine have been reported as VUS and likely pathogenic, respectively (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar). It was reported as homozygous or compound heterozygous with other variants in individuals with purpura fulminans and intracranial hemorrhage (PMID:34654403,28111891,19373522 ) and heterozygous in individuals with deep venous thrombosis (PMID: 19373522 ,18954896). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV004791186	SCV005413498	pathogenic	not provided	2024-04-25	criteria provided, single submitter	clinical testing	PP1_strong, PM1, PM2_moderate, PM3, PM5, PS4_moderate
3billion	RCV000000694	SCV005906188	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive	2023-12-10	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.58 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000659 /PMID: 3185623). A different missense change at the same codon (p.Arg211Gln) has been reported to be associated with PROC related disorder (ClinVar ID: VCV001048661 /PMID: 8499565). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000000693	SCV000020843	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2000-06-01	no assertion criteria provided	literature only
OMIM	RCV000000694	SCV000020844	pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive	2000-06-01	no assertion criteria provided	literature only