VCV000000656.8 - ClinVar

NM_000312.4(PROC):c.1042C>T (p.Arg348Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000312.4(PROC):c.1042C>T (p.Arg348Ter)

Variation ID: 656 Accession: VCV000000656.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q14.3 2: 127428602 (GRCh38) [ NCBI UCSC ] 2: 128186178 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 23, 2016	Feb 14, 2024	Jan 11, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000312.4:c.1042C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000303.1:p.Arg348Ter	nonsense
NM_001375602.1:c.1225C>T	NP_001362531.1:p.Arg409Ter	nonsense
NM_001375603.1:c.1207C>T	NP_001362532.1:p.Arg403Ter	nonsense
NM_001375604.1:c.1105C>T	NP_001362533.1:p.Arg369Ter	nonsense
NM_001375605.1:c.1144C>T	NP_001362534.1:p.Arg382Ter	nonsense
NM_001375606.1:c.1210C>T	NP_001362535.1:p.Arg404Ter	nonsense
NM_001375607.1:c.1228C>T	NP_001362536.1:p.Arg410Ter	nonsense
NM_001375608.1:c.985C>T	NP_001362537.1:p.Arg329Ter	nonsense
NM_001375609.1:c.1018C>T	NP_001362538.1:p.Arg340Ter	nonsense
NM_001375610.1:c.1036C>T	NP_001362539.1:p.Arg346Ter	nonsense
NM_001375611.1:c.1042C>T	NP_001362540.1:p.Arg348Ter	nonsense
NM_001375613.1:c.1042C>T	NP_001362542.1:p.Arg348Ter	nonsense
NC_000002.12:g.127428602C>T
NC_000002.11:g.128186178C>T
NG_016323.1:g.15183C>T
LRG_599:g.15183C>T

... more HGVS ... less HGVS

Protein change

R348*, R329*, R340*, R346*, R369*, R382*, R403*, R404*, R409*, R410*

Other names

R306*

Canonical SPDI

NC_000002.12:127428601:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA114384 OMIM: 612283.0001 dbSNP: rs121918141 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PROC		-	-	GRCh38 GRCh37	375	401

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Thrombophilia due to protein C deficiency, autosomal dominant	Pathogenic (2)	criteria provided, single submitter	Jan 11, 2022	RCV000000690.7
not provided	Pathogenic (2)	no assertion criteria provided	-	RCV001528453.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Thrombophilia due to protein C deficiency, autosomal dominant Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003524951.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 7670104‚ 25039884‚ 29356699‚ 2437584‚ 24122877‚ 26250584‚ 28607330 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PROC protein in which other variant(s) (p.Pro405Alafs20) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PROC protein in which other variant(s) (p.Pro405Alafs20) have been determined to be pathogenic (PMID: 7670104, 25039884, 29356699). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 656). This premature translational stop signal has been observed in individual(s) with autosomal dominant protein C deficiency and autosomal recessive purpura fulminans (PMID: 2437584, 24122877, 26250584, 28607330). This variant is present in population databases (rs121918141, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg348*) in the PROC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the PROC protein. (less)
Pathogenic (Aug 01, 1992)	no assertion criteria provided Method: literature only	THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020840.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016	Publications: PubMed (2) PubMed: 2437584‚ 1511989 Comment on evidence: In affected members of a Dutch pedigree with autosomal dominant thrombophilia due to protein C deficiency (THPH3; 176860), Romeo et al. (1987) identified a heterozygous … (more) In affected members of a Dutch pedigree with autosomal dominant thrombophilia due to protein C deficiency (THPH3; 176860), Romeo et al. (1987) identified a heterozygous mutation in exon 8 of the PROC gene, resulting in an arg306-to-ter (R306X) substitution. Grundy et al. (1992) found the R306X mutation in a Swedish kindred with thrombotic disease. RFLP typing suggested that the Dutch and Swedish mutations were not identical by descent but probably arose as different mutations. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740235.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956208.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PROC protein in which other variant(s) (p.Pro405Alafs*20) have been determined to be pathogenic (PMID: 7670104, 25039884, 29356699). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 656). This premature translational stop signal has been observed in individual(s) with autosomal dominant protein C deficiency and autosomal recessive purpura fulminans (PMID: 2437584, 24122877, 26250584, 28607330). This variant is present in population databases (rs121918141, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg348*) in the PROC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the PROC protein.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A novel compound heterozygous mutations in protein C gene causing neonatal purpura fulminans.	Zhang H	Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis	2018	PMID: 29356699
Genetic characterization of antithrombin, protein C, and protein S deficiencies in Polish patients.	Wypasek E	Polish archives of internal medicine	2017	PMID: 28607330
Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency.	Ichiyama M	Brain & development	2016	PMID: 26250584
Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study.	Limperger V	British journal of haematology	2014	PMID: 25039884
Severe fetal ischaemic brain injury caused by homozygous protein C deficiency.	Stutterd C	Prenatal diagnosis	2014	PMID: 24122877
Identification of mutations in 90 of 121 consecutive symptomatic French patients with a type I protein C deficiency. The French INSERM Network on Molecular Abnormalities Responsible for Protein C and Protein S deficiencies.	Gandrille S	Blood	1995	PMID: 7670104
Two different missense mutations at Arg 178 of the protein C (PROC) gene causing recurrent venous thrombosis.	Grundy CB	Human genetics	1992	PMID: 1511989
Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene.	Romeo G	Proceedings of the National Academy of Sciences of the United States of America	1987	PMID: 2437584

Text-mined citations for rs121918141 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000312.4(PROC):c.1042C>T (p.Arg348Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918141 ...