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NM_000312.4(PROC):c.632G>T (p.Arg211Leu) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Oct 5, 2020
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:
RCV001343833.7

Allele description [Variation Report for NM_000312.4(PROC):c.632G>T (p.Arg211Leu)]

NM_000312.4(PROC):c.632G>T (p.Arg211Leu)

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.632G>T (p.Arg211Leu)
HGVS:
  • NC_000002.12:g.127426181G>T
  • NG_016323.1:g.12762G>T
  • NM_000312.4:c.632G>TMANE SELECT
  • NM_001375602.1:c.815G>T
  • NM_001375603.1:c.797G>T
  • NM_001375604.1:c.695G>T
  • NM_001375605.1:c.734G>T
  • NM_001375606.1:c.800G>T
  • NM_001375607.1:c.818G>T
  • NM_001375608.1:c.575G>T
  • NM_001375609.1:c.608G>T
  • NM_001375610.1:c.626G>T
  • NM_001375611.1:c.632G>T
  • NM_001375613.1:c.632G>T
  • NP_000303.1:p.Arg211Leu
  • NP_001362531.1:p.Arg272Leu
  • NP_001362532.1:p.Arg266Leu
  • NP_001362533.1:p.Arg232Leu
  • NP_001362534.1:p.Arg245Leu
  • NP_001362535.1:p.Arg267Leu
  • NP_001362536.1:p.Arg273Leu
  • NP_001362537.1:p.Arg192Leu
  • NP_001362538.1:p.Arg203Leu
  • NP_001362539.1:p.Arg209Leu
  • NP_001362540.1:p.Arg211Leu
  • NP_001362542.1:p.Arg211Leu
  • LRG_599:g.12762G>T
  • NC_000002.11:g.128183757G>T
Protein change:
R192L
Links:
dbSNP: rs199469476
NCBI 1000 Genomes Browser:
rs199469476
Molecular consequence:
  • NM_000312.4:c.632G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375602.1:c.815G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375603.1:c.797G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375604.1:c.695G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375605.1:c.734G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375606.1:c.800G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375607.1:c.818G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375608.1:c.575G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375609.1:c.608G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375610.1:c.626G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375611.1:c.632G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375613.1:c.632G>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
SCV001537842Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 5, 2020) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular genetic analysis of severe protein C deficiency.

Millar DS, Johansen B, Berntorp E, Minford A, Bolton-Maggs P, Wensley R, Kakkar V, Schulman S, Torres A, Bosch N, Cooper DN.

Hum Genet. 2000 Jun;106(6):646-53.

PubMed [citation]
PMID:
10942114

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene.

Inoue H, Terachi SI, Uchiumi T, Sato T, Urata M, Ishimura M, Koga Y, Hotta T, Hara T, Kang D, Ohga S.

Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26404. Epub 2017 Jan 23.

PubMed [citation]
PMID:
28111891
See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001537842.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

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. This variant disrupts the p.Arg211 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10942114, 28111891, 3185623, 18954896, 24162787, 10805275, 8165644, 18573519). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PROC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 211 of the PROC protein (p.Arg211Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine.

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

Last Updated: Sep 29, 2024