Submissions for variant NM_000312.4(PROC):c.658C>T (p.Arg220Trp)

dbSNP: rs121918152

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000703	SCV002240065	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2023-10-22	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 220 of the PROC protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency (PMID: 1511989, 1868249, 25393254, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg178Trp. ClinVar contains an entry for this variant (Variation ID: 668). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PROC protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Department of Traditional Chinese Medicine, Fujian Provincial Hospital	RCV000000703	SCV005870117	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant		criteria provided, single submitter	research	We found a family with the TSC1 c.363+668G>A mutation exhibited diverse tuberous sclerosis complex (TSC) manifestations. Patient 1 presented with multifocal micronodular pneumocyte hyperplasia (MMPH), lung cancer, shagreen patches, cardiac rhabdomyosarcoma, osteosclerosis, renal cysts, and hamartomas. Patient 2 had renal carcinoma, cysts, and shagreen patches, while Patient 3 showed pulmonary lymphangioleiomyomatosis (LAM) and shagreen patches. RT-qPCR revealed significantly reduced TSC1 mRNA expression in affected individuals. Minigene assays and family segregation analysis confirmed aberrant splicing due to retained intronic sequences in mutant samples, suggesting alternative splicing disruption as the underlying mechanism. This variant contributes to phenotypic variability in TSC1-related disease.
OMIM	RCV000000703	SCV000020853	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	1989-12-25	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004754231	SCV005363317	pathogenic	PROC-related disorder	2024-07-31	no assertion criteria provided	clinical testing	The PROC c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant, described as R178W using legacy nomenclature, segregated with autosomal dominant protein C deficiency in two unrelated families (Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989), although some individuals were symptomatic while others were asymptomatic. This variant has also been observed in the compound heterozygous state in an individual with severe venous thromboembolic disease (Wu et al. 2014. PubMed ID: 25393254) and has been reported along with a second variant in this gene in one individual with protein C deficiency (Tang. et al. 2022. PubMed ID: 35026611). Alternative missense changes at the same amino acid position (i.e. p.Arg220Gly and p.Arg220Gln) have been reported in patients with protein C deficiency (David et al. 2011. PubMed ID: 21621249; Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.