NM_000312.4(PROC):c.552_553insTT (p.Arg185fs) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 9, 2023
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:: RCV000000707.5

Allele description [Variation Report for NM_000312.4(PROC):c.552_553insTT (p.Arg185fs)]

NM_000312.4(PROC):c.552_553insTT (p.Arg185fs)

Gene:

PROC:protein C, inactivator of coagulation factors Va and VIIIa [Gene - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

2q14.3

Genomic location:

Preferred name:

NM_000312.4(PROC):c.552_553insTT (p.Arg185fs)

HGVS:

NC_000002.12:g.127426101_127426102insTT
NG_016323.1:g.12682_12683insTT
NM_000312.4:c.552_553insTTMANE SELECT
NM_001375602.1:c.735_736insTT
NM_001375603.1:c.717_718insTT
NM_001375604.1:c.615_616insTT
NM_001375605.1:c.654_655insTT
NM_001375606.1:c.720_721insTT
NM_001375607.1:c.738_739insTT
NM_001375608.1:c.495_496insTT
NM_001375609.1:c.528_529insTT
NM_001375610.1:c.546_547insTT
NM_001375611.1:c.552_553insTT
NM_001375613.1:c.552_553insTT
NP_000303.1:p.Arg185fs
NP_000303.1:p.Arg185fs
NP_001362531.1:p.Arg246fs
NP_001362532.1:p.Arg240fs
NP_001362533.1:p.Arg206fs
NP_001362534.1:p.Arg219fs
NP_001362535.1:p.Arg241fs
NP_001362536.1:p.Arg247fs
NP_001362537.1:p.Arg166fs
NP_001362538.1:p.Arg177fs
NP_001362539.1:p.Arg183fs
NP_001362540.1:p.Arg185fs
NP_001362542.1:p.Arg185fs
LRG_599t1:c.552_553insTT
LRG_599:g.12682_12683insTT
LRG_599p1:p.Arg185fs
NC_000002.11:g.128183677_128183678insTT
NM_000312.3:c.552_553insTT

Note:

ClinGen staff contributed the HGVS expression for this variant.

Protein change:

R166fs

Links:

OMIM: 612283.0017; dbSNP: rs1558715857

NCBI 1000 Genomes Browser:

rs1558715857

Molecular consequence:

NM_000312.4:c.552_553insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375602.1:c.735_736insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375603.1:c.717_718insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375604.1:c.615_616insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375605.1:c.654_655insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375606.1:c.720_721insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375607.1:c.738_739insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375608.1:c.495_496insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375609.1:c.528_529insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375610.1:c.546_547insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375611.1:c.552_553insTT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375613.1:c.552_553insTT - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000020857	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004293370	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17152060, 1301954, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020857

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1992)

germline

literature only

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

SCV004293370

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 9, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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: identification of a novel two-base pair insertion and two point mutations in exon 7 of the protein C gene in Spanish families.

Soria JM, Fontcuberta J, Borrell M, Estivill X, Sala N.

Hum Mutat. 1992;1(5):428-31.

PubMed [citation]

PMID:: 1301954

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000020857.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In members of a Spanish family with type I, or quantitative, autosomal dominant protein C deficiency (THPH3; 176860), Soria et al. (1992) identified a 2-bp insertion (6139insTT) in the PROC gene, resulting in a frameshift with a stop at codon 156.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004293370.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is also known as 6139,ins TT. This sequence change creates a premature translational stop signal (p.Arg185Leufs*14) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Protein C deficiency disease (PMID: 1301954). ClinVar contains an entry for this variant (Variation ID: 672). 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.

#	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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