Submissions for variant NM_000312.4(PROC):c.659G>A (p.Arg220Gln)

gnomAD frequency: 0.00001  dbSNP: rs121918153

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000000704	SCV000416368	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2017-04-27	criteria provided, single submitter	clinical testing	The PROC c.659G>A (p.Arg220Gln) variant has been reported in six studies in which it is found in a total of 30 individuals with protein C deficiency, all in a heterozygous state (Gandrille et al. 1992; Grundy et al. 1992; Poort et al. 1993; Millar et al. 1995; Soria et al. 1996; Couture et al. 1998). The p.Arg220Gln variant was absent from 50 ethnically matched controls and is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg220Gln 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	RCV000852185	SCV000899857	likely pathogenic	Reduced protein C activity	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000704	SCV001579155	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 220 of the PROC protein (p.Arg220Gln). This variant is present in population databases (rs121918153, gnomAD 0.06%). This missense change has been observed in individuals with protein C deficiency (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg178Gln. ClinVar contains an entry for this variant (Variation ID: 669). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PROC protein function with a negative predictive value of 80%. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been observed in individuals with PROC-related conditions (PMID: 1868249, 2602169, 7605880, 21621249), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV002223748	SCV002502916	pathogenic	not provided	2021-06-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504732	SCV002815549	pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive; Thrombophilia due to protein C deficiency, autosomal dominant	2021-12-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002223748	SCV005413500	pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing	PP1_moderate, PM1, PM2_moderate, PS3_moderate, PS4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000704	SCV005885223	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: PROC c.659G>A (p.Arg220Gln) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251324 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PROC causing Thrombophilia Due To Protein C Deficiency, Autosomal Dominant, allowing no conclusion about variant significance. c.659G>A has been reported in the literature in multiple individuals affected with Thrombophilia Due To Protein C Deficiency, Autosomal Dominant (Grundy_1992, Miyata_2009, Martos_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1511989, 31254973, 18954896, 1868249, 32309994). ClinVar contains an entry for this variant (Variation ID: 669). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000704	SCV000020854	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	1996-01-01	no assertion criteria provided	literature only