NM_000312.4(PROC):c.595C>T (p.Arg199Ter) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001040855.10

Allele description [Variation Report for NM_000312.4(PROC):c.595C>T (p.Arg199Ter)]

NM_000312.4(PROC):c.595C>T (p.Arg199Ter)

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.595C>T (p.Arg199Ter)

HGVS:

NC_000002.12:g.127426144C>T
NG_016323.1:g.12725C>T
NM_000312.4:c.595C>TMANE SELECT
NM_001375602.1:c.778C>T
NM_001375603.1:c.760C>T
NM_001375604.1:c.658C>T
NM_001375605.1:c.697C>T
NM_001375606.1:c.763C>T
NM_001375607.1:c.781C>T
NM_001375608.1:c.538C>T
NM_001375609.1:c.571C>T
NM_001375610.1:c.589C>T
NM_001375611.1:c.595C>T
NM_001375613.1:c.595C>T
NP_000303.1:p.Arg199Ter
NP_001362531.1:p.Arg260Ter
NP_001362532.1:p.Arg254Ter
NP_001362533.1:p.Arg220Ter
NP_001362534.1:p.Arg233Ter
NP_001362535.1:p.Arg255Ter
NP_001362536.1:p.Arg261Ter
NP_001362537.1:p.Arg180Ter
NP_001362538.1:p.Arg191Ter
NP_001362539.1:p.Arg197Ter
NP_001362540.1:p.Arg199Ter
NP_001362542.1:p.Arg199Ter
LRG_599t1:c.595C>T
LRG_599:g.12725C>T
NC_000002.11:g.128183720C>T
NM_000312.3:c.595C>T

Protein change:

R180*

Links:

dbSNP: rs1456533664

NCBI 1000 Genomes Browser:

rs1456533664

Molecular consequence:

NM_000312.4:c.595C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375602.1:c.778C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375603.1:c.760C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375604.1:c.658C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375605.1:c.697C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375606.1:c.763C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375607.1:c.781C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375608.1:c.538C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375609.1:c.571C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375610.1:c.589C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375611.1:c.595C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375613.1:c.595C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001204446	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17152060, 7894031, 24028705, 25648792, 28492532
SCV001786602	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Oct 30, 2020)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21621249, 24028705, 25533856, 25648792 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001204446

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001786602

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Oct 30, 2020)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C.

Rovida E, Merati G, D'Ursi P, Zanardelli S, Marino F, Fontana G, Castaman G, Faioni EM.

Hum Mutat. 2007 Apr;28(4):345-55.

PubMed [citation]

PMID:: 17152060

Protein C deficiency found in a patient with acute myocardial infarction: a single base mutation 157 Arg (CGA) to stop codon (TGA).

Nakagawa K, Tsuji H, Masuda H, Kitamura H, Nakahara Y, Ogasahara Y, Okajima Y, Sawada S, Nakagawa M.

Int J Hematol. 1994 Dec;60(4):273-80.

PubMed [citation]

PMID:: 7894031

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001204446.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg199*) in the PROC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROC are known to be pathogenic (PMID: 17152060). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with protein C deficiency (PMID: 7894031, 24028705, 25648792). This variant is also known as 6182 C>T (157Arg). ClinVar contains an entry for this variant (Variation ID: 839161). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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 Illumina Laboratory Services, Illumina, SCV001786602.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Across a selection of the available literature, the PROC c.595C>T (p.Arg199Ter) variant, a stop-gained variant, has been identified in a heterozygous state in at least eleven unrelated families with protein C deficiency and a history of venous thrombosis, and in a compound heterozygous state in one individual with protein C deficiency (David et al. 2011; Fidalgo et al. 2014; Luan et al. 2015). The p.Arg199Ter variant was also found in a patient with venous thromboembolism and protein C deficiency who also carried a PROC missense variant, but the phase of variants was not provided (Gu et al. 2014). The p.Arg199Ter variant is reported at a frequency of 0.000007 in the Total population of the Genome Aggregation Database, but this is based on two alleles in a region of good sequencing coverage so the variant is presumed to be rare. In vitro studies demonstrated that the p.Arg199Ter variant affects protein C function via nonsense mediated decay (Luan et al. 2015). Based on the collective evidence and application of the ACMG criteria, the p.Arg199Ter variant is classified as pathogenic for protein C deficiency.

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

Last Updated: Aug 4, 2024

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