NM_000312.4(PROC):c.340G>C (p.Gly114Arg) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 31, 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:: RCV000148747.7

Allele description [Variation Report for NM_000312.4(PROC):c.340G>C (p.Gly114Arg)]

NM_000312.4(PROC):c.340G>C (p.Gly114Arg)

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.340G>C (p.Gly114Arg)

HGVS:

NC_000002.12:g.127423111G>C
NG_016323.1:g.9692G>C
NM_000312.4:c.340G>CMANE SELECT
NM_001375602.1:c.523G>C
NM_001375603.1:c.403G>C
NM_001375604.1:c.403G>C
NM_001375605.1:c.340G>C
NM_001375606.1:c.495G>C
NM_001375607.1:c.424G>C
NM_001375608.1:c.340G>C
NM_001375609.1:c.316G>C
NM_001375610.1:c.334G>C
NM_001375611.1:c.340G>C
NM_001375613.1:c.340G>C
NP_000303.1:p.Gly114Arg
NP_000303.1:p.Gly114Arg
NP_001362531.1:p.Gly175Arg
NP_001362532.1:p.Gly135Arg
NP_001362533.1:p.Gly135Arg
NP_001362534.1:p.Gly114Arg
NP_001362535.1:p.Thr165=
NP_001362536.1:p.Gly142Arg
NP_001362537.1:p.Gly114Arg
NP_001362538.1:p.Gly106Arg
NP_001362539.1:p.Gly112Arg
NP_001362540.1:p.Gly114Arg
NP_001362542.1:p.Gly114Arg
LRG_599t1:c.340G>C
LRG_599:g.9692G>C
LRG_599p1:p.Gly114Arg
NC_000002.11:g.128180687G>C
NM_000312.3:c.340G>C
P04070:p.Gly114Arg

Protein change:

G106R

Links:

UniProtKB: P04070#VAR_006651; dbSNP: rs374476971

NCBI 1000 Genomes Browser:

rs374476971

Molecular consequence:

NM_000312.4:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375602.1:c.523G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375603.1:c.403G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375604.1:c.403G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375605.1:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375607.1:c.424G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375608.1:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375609.1:c.316G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375610.1:c.334G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375611.1:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375613.1:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375606.1:c.495G>C - synonymous variant - [Sequence Ontology: SO:0001819]

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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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190484	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV002258134	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 31, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 7792728, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190484

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV002258134

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 31, 2021)

germline

clinical testing

PubMed (2)
[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

Six different point mutations in seven Danish families with symptomatic protein C deficiency.

Lind B, Schwartz M, Thorsen S.

Thromb Haemost. 1995 Feb;73(2):186-93.

PubMed [citation]

PMID:: 7792728

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190484.1

#	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, SCV002258134.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 161341). This variant is also known as p.Gly72Arg. This missense change has been observed in individual(s) with protein C deficiency (PMID: 7792728). This variant is present in population databases (rs374476971, ExAC 0.005%). This sequence change replaces glycine with arginine at codon 114 of the PROC protein (p.Gly114Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine.

#	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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