NM_000312.4(PROC):c.935C>T (p.Ser312Leu) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jun 27, 2022
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:
RCV000000715.11

Allele description [Variation Report for NM_000312.4(PROC):c.935C>T (p.Ser312Leu)]

NM_000312.4(PROC):c.935C>T (p.Ser312Leu)

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.935C>T (p.Ser312Leu)
Other names:
S270L
HGVS:
  • NC_000002.12:g.127428495C>T
  • NG_016323.1:g.15076C>T
  • NM_000312.4:c.935C>TMANE SELECT
  • NM_001375602.1:c.1118C>T
  • NM_001375603.1:c.1100C>T
  • NM_001375604.1:c.998C>T
  • NM_001375605.1:c.1037C>T
  • NM_001375606.1:c.1103C>T
  • NM_001375607.1:c.1121C>T
  • NM_001375608.1:c.878C>T
  • NM_001375609.1:c.911C>T
  • NM_001375610.1:c.929C>T
  • NM_001375611.1:c.935C>T
  • NM_001375613.1:c.935C>T
  • NP_000303.1:p.Ser312Leu
  • NP_000303.1:p.Ser312Leu
  • NP_001362531.1:p.Ser373Leu
  • NP_001362532.1:p.Ser367Leu
  • NP_001362533.1:p.Ser333Leu
  • NP_001362534.1:p.Ser346Leu
  • NP_001362535.1:p.Ser368Leu
  • NP_001362536.1:p.Ser374Leu
  • NP_001362537.1:p.Ser293Leu
  • NP_001362538.1:p.Ser304Leu
  • NP_001362539.1:p.Ser310Leu
  • NP_001362540.1:p.Ser312Leu
  • NP_001362542.1:p.Ser312Leu
  • LRG_599t1:c.935C>T
  • LRG_599:g.15076C>T
  • LRG_599p1:p.Ser312Leu
  • NC_000002.11:g.128186071C>T
  • NM_000312.3:c.935C>T
  • P04070:p.Ser312Leu
Protein change:
S293L; SER270LEU
Links:
UniProtKB: P04070#VAR_006685; OMIM: 612283.0025; dbSNP: rs121918160
NCBI 1000 Genomes Browser:
rs121918160
Molecular consequence:
  • NM_000312.4:c.935C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375602.1:c.1118C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375603.1:c.1100C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375604.1:c.998C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375605.1:c.1037C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375606.1:c.1103C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375607.1:c.1121C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375608.1:c.878C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375609.1:c.911C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375610.1:c.929C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375611.1:c.935C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375613.1:c.935C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000020865OMIM
no assertion criteria provided
Pathogenic
(Jun 1, 2001) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000646390Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jun 27, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

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

Symptomatic type 1 protein C deficiency caused by a de novo Ser270Leu mutation in the catalytic domain.

Lind B, Koefoed P, Thorsen S.

Br J Haematol. 2001 Jun;113(3):642-8.

PubMed [citation]
PMID:
11380450
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000020865.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Lind et al. (2001) found heterozygosity for an 8524C-T transition in the PROC gene, resulting in a ser270-to-leu (S270L) substitution in affected members of a family with venous thrombosis (THPH3; 176860). The mutation was associated with parallel reduction in plasma levels of protein C anticoagulant activity and protein C antigen, consistent with type I deficiency. Transient expression of mutant protein C cDNA in human kidney 293 cells and analysis of protein C antigen in culture media and cell lysates showed that the secretion of mutant protein compared with wildtype was reduced by at least 97%, whereas the intracellular content of mutant and wildtype protein was similar. Northern blot analysis of total mRNA from transfected cells showed no reduction of the mutant protein C mRNA compared with wildtype. The proband, a female, suffered at the ages of 17 and 24 years from deep vein thrombosis complicated by bilateral pulmonary embolism. The mutation appeared to be de novo. Unexplained was the fact that the mother had suffered an attack of pulmonary embolism at the age of 45 years, 3 weeks after provoked abortion, laparoscopy, and exploratory laparotomy. The mother had a normal protein C genotype and plasma phenotype and did not have the arg506-to-gln Leiden mutation in coagulation factor V (612309.0001) or the 20210G-A mutation in the prothrombin gene (176930.0009).

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000646390.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PROC function (PMID: 11380450). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 680). This variant is also known as 8524C>T, p.Ser270Leu. This missense change has been observed in individuals with deep vein thrombosis, pulmonary embolism, and protein C deficiency (PMID: 7482420, 11380450, 22545135). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918160, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 312 of the PROC protein (p.Ser312Leu).

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

Last Updated: Sep 29, 2024