ClinVar Genomic variation as it relates to human health
NM_000312.4(PROC):c.631C>T (p.Arg211Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000312.4(PROC):c.631C>T (p.Arg211Trp)
Variation ID: 659 Accession: VCV000000659.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q14.3 2: 127426180 (GRCh38) [ NCBI UCSC ] 2: 128183756 (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 11, 2015 Apr 15, 2024 Apr 4, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000312.4:c.631C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000303.1:p.Arg211Trp missense NM_001375602.1:c.814C>T NP_001362531.1:p.Arg272Trp missense NM_001375603.1:c.796C>T NP_001362532.1:p.Arg266Trp missense NM_001375604.1:c.694C>T NP_001362533.1:p.Arg232Trp missense NM_001375605.1:c.733C>T NP_001362534.1:p.Arg245Trp missense NM_001375606.1:c.799C>T NP_001362535.1:p.Arg267Trp missense NM_001375607.1:c.817C>T NP_001362536.1:p.Arg273Trp missense NM_001375608.1:c.574C>T NP_001362537.1:p.Arg192Trp missense NM_001375609.1:c.607C>T NP_001362538.1:p.Arg203Trp missense NM_001375610.1:c.625C>T NP_001362539.1:p.Arg209Trp missense NM_001375611.1:c.631C>T NP_001362540.1:p.Arg211Trp missense NM_001375613.1:c.631C>T NP_001362542.1:p.Arg211Trp missense NC_000002.12:g.127426180C>T NC_000002.11:g.128183756C>T NG_016323.1:g.12761C>T LRG_599:g.12761C>T LRG_599t1:c.631C>T LRG_599p1:p.Arg211Trp P04070:p.Arg211Trp - Protein change
- R211W, R192W, R203W, R209W, R232W, R245W, R266W, R267W, R272W, R273W
- Other names
- R169W
- Canonical SPDI
- NC_000002.12:127426179:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
---|---|---|---|---|---|---|
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 |
374 | 400 |
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, single submitter
|
Apr 4, 2024 | RCV000000694.6 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 14, 2023 | RCV000000693.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2019 | RCV000851836.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jun 01, 2014)
|
criteria provided, single submitter
Method: research
|
Protein C deficiency
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190475.2 First in ClinVar: Dec 06, 2014 Last updated: Oct 11, 2015
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
|
|
Likely pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: research
|
Reduced protein C activity
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899837.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: female
Ethnicity/Population group: European
|
|
Pathogenic
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Thrombophilia due to protein C deficiency, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000817071.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs121918143, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence … (more)
This variant is present in population databases (rs121918143, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROC protein function. ClinVar contains an entry for this variant (Variation ID: 659). This variant is also known as Arg157Trp or Arg169Trp. This missense change has been observed in individuals with purpura fulminans and severe protein C deficiency and venous thromboembolism and partial protein C deficiency (PMID: 3185623, 8165644, 10805275, 10942114, 18573519, 18954896, 24162787, 28111891). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 211 of the PROC protein (p.Arg211Trp). (less)
|
|
Likely pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Thrombophilia due to protein C deficiency, autosomal recessive
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809565.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
Pathogenic
(Jun 01, 2000)
|
no assertion criteria provided
Method: literature only
|
THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020843.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
Matsuda et al. (1988) and Grundy et al. (1989) identified a protein C variant, called 'Tochigi' and 'London-1,' respectively, in which a C-to-T transition in … (more)
Matsuda et al. (1988) and Grundy et al. (1989) identified a protein C variant, called 'Tochigi' and 'London-1,' respectively, in which a C-to-T transition in the PROC gene resulted in an arg169-to-trp (R169W) substitution. The change occurred in the thrombin activation site in exon 7 and resulted in autosomal dominant thrombotic disease (THPH3; 176860). This recurrent mutation occurred at a CpG dinucleotide. Millar et al. (2000) identified a homozygous R169W mutation in a patient with severe autosomal recessive protein C deficiency (THPH4; 612304) manifest as neonatal purpura fulminans. (less)
|
|
Pathogenic
(Jun 01, 2000)
|
no assertion criteria provided
Method: literature only
|
THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020844.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
Matsuda et al. (1988) and Grundy et al. (1989) identified a protein C variant, called 'Tochigi' and 'London-1,' respectively, in which a C-to-T transition in … (more)
Matsuda et al. (1988) and Grundy et al. (1989) identified a protein C variant, called 'Tochigi' and 'London-1,' respectively, in which a C-to-T transition in the PROC gene resulted in an arg169-to-trp (R169W) substitution. The change occurred in the thrombin activation site in exon 7 and resulted in autosomal dominant thrombotic disease (THPH3; 176860). This recurrent mutation occurred at a CpG dinucleotide. Millar et al. (2000) identified a homozygous R169W mutation in a patient with severe autosomal recessive protein C deficiency (THPH4; 612304) manifest as neonatal purpura fulminans. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene. | Inoue H | Pediatric blood & cancer | 2017 | PMID: 28111891 |
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 | Haematologica | 2014 | PMID: 24162787 |
Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. | Miyata T | Thrombosis research | 2009 | PMID: 18954896 |
Severe protein C deficiency from compound heterozygous mutations in the PROC gene in two Korean adult patients. | Kim HJ | Thrombosis research | 2008 | PMID: 18573519 |
Molecular genetic analysis of severe protein C deficiency. | Millar DS | Human genetics | 2000 | PMID: 10942114 |
Studies on congenital protein C deficiency in Japanese: prevalence, genetic analysis, and relevance to the onset of arterial occlusive diseases. | Sakata T | Seminars in thrombosis and hemostasis | 2000 | PMID: 10805275 |
Three missense mutations in the protein C heavy chain causing type I and type II protein C deficiency. | Miyata T | Thrombosis and haemostasis | 1994 | PMID: 8165644 |
A novel homozygous missense mutation in the protein C (PROC) gene causing recurrent venous thrombosis. | Grundy CB | Human genetics | 1992 | PMID: 1511988 |
A thrombotic state due to an abnormal protein C. | Matsuda M | The New England journal of medicine | 1988 | PMID: 3185623 |
Text-mined citations for rs121918143 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.