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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:
RCV001040855.11

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001204446Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 3, 2023) 		germlineclinical testing

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

SCV001786602Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)		Pathogenic
(Oct 30, 2020) 		unknownclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001204446.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV001786602.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024