NM_000312.4(PROC):c.962C>T (p.Pro321Leu) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 28, 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:: RCV000689154.7

Allele description [Variation Report for NM_000312.4(PROC):c.962C>T (p.Pro321Leu)]

NM_000312.4(PROC):c.962C>T (p.Pro321Leu)

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.962C>T (p.Pro321Leu)

HGVS:

NC_000002.12:g.127428522C>T
NG_016323.1:g.15103C>T
NM_000312.4:c.962C>TMANE SELECT
NM_001375602.1:c.1145C>T
NM_001375603.1:c.1127C>T
NM_001375604.1:c.1025C>T
NM_001375605.1:c.1064C>T
NM_001375606.1:c.1130C>T
NM_001375607.1:c.1148C>T
NM_001375608.1:c.905C>T
NM_001375609.1:c.938C>T
NM_001375610.1:c.956C>T
NM_001375611.1:c.962C>T
NM_001375613.1:c.962C>T
NP_000303.1:p.Pro321Leu
NP_000303.1:p.Pro321Leu
NP_001362531.1:p.Pro382Leu
NP_001362532.1:p.Pro376Leu
NP_001362533.1:p.Pro342Leu
NP_001362534.1:p.Pro355Leu
NP_001362535.1:p.Pro377Leu
NP_001362536.1:p.Pro383Leu
NP_001362537.1:p.Pro302Leu
NP_001362538.1:p.Pro313Leu
NP_001362539.1:p.Pro319Leu
NP_001362540.1:p.Pro321Leu
NP_001362542.1:p.Pro321Leu
LRG_599t1:c.962C>T
LRG_599:g.15103C>T
LRG_599p1:p.Pro321Leu
NC_000002.11:g.128186098C>T
NM_000312.3:c.962C>T

Protein change:

P302L

Links:

dbSNP: rs1321566264

NCBI 1000 Genomes Browser:

rs1321566264

Molecular consequence:

NM_000312.4:c.962C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375602.1:c.1145C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375603.1:c.1127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375604.1:c.1025C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375605.1:c.1064C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375606.1:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375607.1:c.1148C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375608.1:c.905C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375609.1:c.938C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375610.1:c.956C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375611.1:c.962C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001375613.1:c.962C>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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malonate--CoA ligase ACSF3, mitochondrial [Cuculus canorus]
malonate--CoA ligase ACSF3, mitochondrial [Cuculus canorus]
gi|2452540131|ref|XP_053934512.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000816794	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8499565, 17152060, 31254973, 28492532
SCV002556901	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000816794

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 28, 2023)

germline

clinical testing

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

SCV002556901

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 26, 2019)

germline

clinical testing

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

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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency.

Poort SR, Pabinger-Fasching I, Mannhalter C, Reitsma PH, Bertina RM.

Blood Coagul Fibrinolysis. 1993 Apr;4(2):273-80.

PubMed [citation]

PMID:: 8499565

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000816794.4

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 321 of the PROC protein (p.Pro321Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with protein C deficiency (PMID: 8499565, 17152060, 31254973; Invitae). This variant is also known as p.Pro279Leu. ClinVar contains an entry for this variant (Variation ID: 568712). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PROC protein function with a positive predictive value of 80%. 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 Genetics and Molecular Pathology, SA Pathology, SCV002556901.2

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

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

Last Updated: Sep 29, 2024

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