NM_000312.4(PROC):c.629C>T (p.Pro210Leu) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 16, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000778563.11

Allele description [Variation Report for NM_000312.4(PROC):c.629C>T (p.Pro210Leu)]

NM_000312.4(PROC):c.629C>T (p.Pro210Leu)

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.629C>T (p.Pro210Leu)

Other names:

P168L

HGVS:

NC_000002.12:g.127426178C>T
NG_016323.1:g.12759C>T
NM_000312.4:c.629C>TMANE SELECT
NM_001375602.1:c.812C>T
NM_001375603.1:c.794C>T
NM_001375604.1:c.692C>T
NM_001375605.1:c.731C>T
NM_001375606.1:c.797C>T
NM_001375607.1:c.815C>T
NM_001375608.1:c.572C>T
NM_001375609.1:c.605C>T
NM_001375610.1:c.623C>T
NM_001375611.1:c.629C>T
NM_001375613.1:c.629C>T
NP_000303.1:p.Pro210Leu
NP_000303.1:p.Pro210Leu
NP_001362531.1:p.Pro271Leu
NP_001362532.1:p.Pro265Leu
NP_001362533.1:p.Pro231Leu
NP_001362534.1:p.Pro244Leu
NP_001362535.1:p.Pro266Leu
NP_001362536.1:p.Pro272Leu
NP_001362537.1:p.Pro191Leu
NP_001362538.1:p.Pro202Leu
NP_001362539.1:p.Pro208Leu
NP_001362540.1:p.Pro210Leu
NP_001362542.1:p.Pro210Leu
LRG_599t1:c.629C>T
LRG_599:g.12759C>T
LRG_599p1:p.Pro210Leu
NC_000002.11:g.128183754C>T
NM_000312.3:c.629C>T
P04070:p.Pro210Leu

Protein change:

P191L; PRO168LEU

Links:

UniProtKB: P04070#VAR_006664; OMIM: 612283.0006; dbSNP: rs121918145

NCBI 1000 Genomes Browser:

rs121918145

Molecular consequence:

NM_000312.4:c.629C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375602.1:c.812C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375603.1:c.794C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375604.1:c.692C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375605.1:c.731C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375606.1:c.797C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375607.1:c.815C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375608.1:c.572C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375609.1:c.605C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375610.1:c.623C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375611.1:c.629C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375613.1:c.629C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914865	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Nov 15, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21621249, 7482420, 24162787, 1347608 Citation Link,
SCV002243051	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 16, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1347608, 18573519, 21621249, 7482420, 31254973, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000914865

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Nov 15, 2018)

germline

clinical testing

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

Citation Link,

SCV002243051

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 16, 2021)

germline

clinical testing

PubMed (6)
[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

Citations

PubMed

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population.

Kim HJ, Seo JY, Lee KO, Bang SH, Lee ST, Ki CS, Kim JW, Jung CW, Kim DK, Kim SH.

Haematologica. 2014 Mar;99(3):561-9. doi: 10.3324/haematol.2013.092023. Epub 2013 Oct 25.

PubMed [citation]

PMID:: 24162787
PMCID:: PMC3943322

Homozygous protein C deficiency with late onset and recurrent coumarin-induced skin necrosis.

Conard J, Horellou MH, van Dreden P, Samama M, Reitsma PH, Poort S, Bertina RM.

Lancet. 1992 Mar 21;339(8795):743-4. No abstract available.

PubMed [citation]

PMID:: 1347608

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914865.1

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

Description

The PROC c.629C>T (p.Pro210Leu) missense variant has been reported in four studies and is found in a total of 12 individuals with protein C deficiency including two in a homozygous state, one in a compound heterozygous state, and at least nine in a heterozygous state (Conard et al. 1992; Reitsma et al. 1995; David et al. 2011; Kim et al. 2014). One homozygous patient had at least six unaffected family members who carried the variant in a heterozygous state (Conard et al. 1992). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele only so the variant is presumed to be rare. Based on the evidence, the p.Pro210Leu variant is classified as a variant of unknown significance but suspicious of pathogenicity for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV002243051.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with protein C deficiency (PMID: 1347608, 18573519, 21621249, 7482420, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as 6216C>T; Pro168Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 661). This variant is present in population databases (rs121918145, ExAC 0.002%). This sequence change replaces proline with leucine at codon 210 of the PROC protein (p.Pro210Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine.

#	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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