This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PROC protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency (PMID: 1511989, 1868249, 25393254, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg178Trp. ClinVar contains an entry for this variant (Variation ID: 668). 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 not expected to disrupt PROC protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000312.4(PROC):c.658C>T (p.Arg220Trp)
Germline
Classification
Help
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.
(3)
Help
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
3
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.658C>T (p.Arg220Trp)
Variation ID: 668 Accession: VCV000000668.5
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q14.3 2: 127426207 (GRCh38) [ NCBI UCSC ] 2: 128183783 (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 Oct 8, 2024 Oct 22, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000312.4:c.658C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000303.1:p.Arg220Trp missense NM_000312.3:c.658C>T NM_001375602.1:c.841C>T NP_001362531.1:p.Arg281Trp missense NM_001375603.1:c.823C>T NP_001362532.1:p.Arg275Trp missense NM_001375604.1:c.721C>T NP_001362533.1:p.Arg241Trp missense NM_001375605.1:c.760C>T NP_001362534.1:p.Arg254Trp missense NM_001375606.1:c.826C>T NP_001362535.1:p.Arg276Trp missense NM_001375607.1:c.844C>T NP_001362536.1:p.Arg282Trp missense NM_001375608.1:c.601C>T NP_001362537.1:p.Arg201Trp missense NM_001375609.1:c.634C>T NP_001362538.1:p.Arg212Trp missense NM_001375610.1:c.652C>T NP_001362539.1:p.Arg218Trp missense NM_001375611.1:c.658C>T NP_001362540.1:p.Arg220Trp missense NM_001375613.1:c.658C>T NP_001362542.1:p.Arg220Trp missense NC_000002.12:g.127426207C>T NC_000002.11:g.128183783C>T NG_016323.1:g.12788C>T LRG_599:g.12788C>T LRG_599t1:c.658C>T P04070:p.Arg220Trp - Protein change
- R220W, R201W, R212W, R218W, R241W, R254W, R275W, R276W, R281W, R282W
- Other names
-
R178W
- Canonical SPDI
- NC_000002.12:127426206: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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Oct 22, 2023 | RCV000000703.8 | |
|
PROC-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 31, 2024 | RCV004754231.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 22, 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: SCV002240065.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PROC protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PROC protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency (PMID: 1511989, 1868249, 25393254, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg178Trp. ClinVar contains an entry for this variant (Variation ID: 668). 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 not expected to disrupt PROC protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 25, 1989)
|
no assertion criteria provided
Method: literature only
|
THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020853.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In a patient with autosomal dominant thrombophilia (THPH3; 176860), Grundy et al. (1992) identified a heterozygous C-to-T transition in the PROC gene, resulting in an … (more)
In a patient with autosomal dominant thrombophilia (THPH3; 176860), Grundy et al. (1992) identified a heterozygous C-to-T transition in the PROC gene, resulting in an arg178-to-trp (R178W) substitution. The mutation was found in a Swedish family in which the propositus, who had 30% of normal protein C activity, experienced recurrent deep venous thrombosis. (less)
|
|
|
Pathogenic
(Jul 31, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PROC-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005363317.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The PROC c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant, described as R178W using legacy nomenclature, segregated with autosomal … (more)
The PROC c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant, described as R178W using legacy nomenclature, segregated with autosomal dominant protein C deficiency in two unrelated families (Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989), although some individuals were symptomatic while others were asymptomatic. This variant has also been observed in the compound heterozygous state in an individual with severe venous thromboembolic disease (Wu et al. 2014. PubMed ID: 25393254) and has been reported along with a second variant in this gene in one individual with protein C deficiency (Tang. et al. 2022. PubMed ID: 35026611). Alternative missense changes at the same amino acid position (i.e. p.Arg220Gly and p.Arg220Gln) have been reported in patients with protein C deficiency (David et al. 2011. PubMed ID: 21621249; Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
The PROC c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant, described as R178W using legacy nomenclature, segregated with autosomal dominant protein C deficiency in two unrelated families (Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989), although some individuals were symptomatic while others were asymptomatic. This variant has also been observed in the compound heterozygous state in an individual with severe venous thromboembolic disease (Wu et al. 2014. PubMed ID: 25393254) and has been reported along with a second variant in this gene in one individual with protein C deficiency (Tang. et al. 2022. PubMed ID: 35026611). Alternative missense changes at the same amino acid position (i.e. p.Arg220Gly and p.Arg220Gln) have been reported in patients with protein C deficiency (David et al. 2011. PubMed ID: 21621249; Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
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:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PROC protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency (PMID: 1511989, 1868249, 25393254, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg178Trp. ClinVar contains an entry for this variant (Variation ID: 668). 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 not expected to disrupt PROC protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The PROC c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant, described as R178W using legacy nomenclature, segregated with autosomal dominant protein C deficiency in two unrelated families (Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989), although some individuals were symptomatic while others were asymptomatic. This variant has also been observed in the compound heterozygous state in an individual with severe venous thromboembolic disease (Wu et al. 2014. PubMed ID: 25393254) and has been reported along with a second variant in this gene in one individual with protein C deficiency (Tang. et al. 2022. PubMed ID: 35026611). Alternative missense changes at the same amino acid position (i.e. p.Arg220Gly and p.Arg220Gln) have been reported in patients with protein C deficiency (David et al. 2011. PubMed ID: 21621249; Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of 58 Mutations (26 Novel) in 94 of 109 Symptomatic Spanish Probands with Protein C Deficiency. | Martos L | Thrombosis and haemostasis | 2019 | PMID: 31254973 |
| Hereditary protein C deficiency caused by compound heterozygous mutants in two independent Chinese families. | Wu YT | Pathology | 2014 | PMID: 25393254 |
| 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 |
| Three novel mutations in the protein C (PROC) gene causing venous thrombosis. | Millar DS | Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis | 1995 | PMID: 7605880 |
| Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency. | Poort SR | Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis | 1993 | PMID: 8499565 |
| Two different missense mutations at Arg 178 of the protein C (PROC) gene causing recurrent venous thrombosis. | Grundy CB | Human genetics | 1992 | PMID: 1511989 |
| Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis. | Gandrille S | Human mutation | 1992 | PMID: 1301959 |
| 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 | Human mutation | 1992 | PMID: 1301954 |
| The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. | Reitsma PH | Blood | 1991 | PMID: 1868249 |
| Protein C London 1: recurrent mutation at Arg 169 (CGG----TGG) in the protein C gene causing thrombosis. | Grundy C | Nucleic acids research | 1989 | PMID: 2602169 |
Text-mined citations for rs121918152 ...
HelpThese 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 Oct 13, 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.