NM_000312.4(PROC):c.580C>T (p.Arg194Cys) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 13, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000148745.9

Allele description [Variation Report for NM_000312.4(PROC):c.580C>T (p.Arg194Cys)]

NM_000312.4(PROC):c.580C>T (p.Arg194Cys)

Gene:

PROC:protein C, inactivator of coagulation factors Va and VIIIa [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q14.3

Genomic location:

Preferred name:

NM_000312.4(PROC):c.580C>T (p.Arg194Cys)

HGVS:

NC_000002.12:g.127426129C>T
NG_016323.1:g.12710C>T
NM_000312.4:c.580C>TMANE SELECT
NM_001375602.1:c.763C>T
NM_001375603.1:c.745C>T
NM_001375604.1:c.643C>T
NM_001375605.1:c.682C>T
NM_001375606.1:c.748C>T
NM_001375607.1:c.766C>T
NM_001375608.1:c.523C>T
NM_001375609.1:c.556C>T
NM_001375610.1:c.574C>T
NM_001375611.1:c.580C>T
NM_001375613.1:c.580C>T
NP_000303.1:p.Arg194Cys
NP_000303.1:p.Arg194Cys
NP_001362531.1:p.Arg255Cys
NP_001362532.1:p.Arg249Cys
NP_001362533.1:p.Arg215Cys
NP_001362534.1:p.Arg228Cys
NP_001362535.1:p.Arg250Cys
NP_001362536.1:p.Arg256Cys
NP_001362537.1:p.Arg175Cys
NP_001362538.1:p.Arg186Cys
NP_001362539.1:p.Arg192Cys
NP_001362540.1:p.Arg194Cys
NP_001362542.1:p.Arg194Cys
LRG_599t1:c.580C>T
LRG_599:g.12710C>T
LRG_599p1:p.Arg194Cys
NC_000002.11:g.128183705C>T
NM_000312.3:c.580C>T
P04070:p.Arg194Cys

Protein change:

R175C

Links:

UniProtKB: P04070#VAR_006663; dbSNP: rs371071104

NCBI 1000 Genomes Browser:

rs371071104

Molecular consequence:

NM_000312.4:c.580C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375602.1:c.763C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375603.1:c.745C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375604.1:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375605.1:c.682C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375606.1:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375607.1:c.766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375608.1:c.523C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375609.1:c.556C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375610.1:c.574C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375611.1:c.580C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375613.1:c.580C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Thrombophilia due to protein C deficiency, autosomal dominant
Synonyms:: PROC DEFICIENCY, AUTOSOMAL DOMINANT; PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT; Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant
Identifiers:: MONDO: MONDO:0008316; MedGen: C2674321; Orphanet: 745; OMIM: 176860

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190482	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000284567	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 13, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7482420, 27517348, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190482

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV000284567

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 13, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH.

Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, et al.

Thromb Haemost. 1995 May;73(5):876-89. Review. No abstract available.

PubMed [citation]

PMID:: 7482420

Two novel compound heterozygous mutations associated with types I and II protein C deficiency with unusual phenotypes.

Deng MY, Liu ZX, Huang HF, Chen YH, Luo YJ, Sun NN, Cheng Z, Yan WZ, Zhang GS.

Thromb Res. 2016 Sep;145:93-9. doi: 10.1016/j.thromres.2016.08.005. Epub 2016 Aug 3.

PubMed [citation]

PMID:: 27517348

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190482.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284567.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine with cysteine at codon 194 of the PROC protein (p.Arg194Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs371071104, ExAC 0.009%). This missense change has been observed in individuals with protein C deficiency (PMID: 7482420, 27517348). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PROC function (PMID: 27517348). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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