VCV000188230.20 - ClinVar

NM_000312.4(PROC):c.169C>T (p.Arg57Trp)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000312.4(PROC):c.169C>T (p.Arg57Trp)

Variation ID: 188230 Accession: VCV000188230.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q14.3 2: 127421381 (GRCh38) [ NCBI UCSC ] 2: 128178957 (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	May 22, 2017	Feb 20, 2024	Dec 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000312.4:c.169C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000303.1:p.Arg57Trp	missense
NM_001375602.1:c.352C>T	NP_001362531.1:p.Arg118Trp	missense
NM_001375603.1:c.232C>T	NP_001362532.1:p.Arg78Trp	missense
NM_001375604.1:c.232C>T	NP_001362533.1:p.Arg78Trp	missense
NM_001375605.1:c.169C>T	NP_001362534.1:p.Arg57Trp	missense
NM_001375606.1:c.232C>T	NP_001362535.1:p.Arg78Trp	missense
NM_001375607.1:c.253C>T	NP_001362536.1:p.Arg85Trp	missense
NM_001375608.1:c.169C>T	NP_001362537.1:p.Arg57Trp	missense
NM_001375609.1:c.145C>T	NP_001362538.1:p.Arg49Trp	missense
NM_001375610.1:c.163C>T	NP_001362539.1:p.Arg55Trp	missense
NM_001375611.1:c.169C>T	NP_001362540.1:p.Arg57Trp	missense
NM_001375613.1:c.169C>T	NP_001362542.1:p.Arg57Trp	missense
NC_000002.12:g.127421381C>T
NC_000002.11:g.128178957C>T
NG_016323.1:g.7962C>T
LRG_599:g.7962C>T
LRG_599t1:c.169C>T	LRG_599p1:p.Arg57Trp
	P04070:p.Arg57Trp

... more HGVS ... less HGVS

Protein change

R57W, R118W, R49W, R55W, R78W, R85W

Other names

Canonical SPDI

NC_000002.12:127421380: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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA334388 UniProtKB: P04070#VAR_006642 dbSNP: rs757583846 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/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 12, 2023	RCV000168170.12
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jun 8, 2015	RCV000490205.8
Thrombophilia due to protein C deficiency, autosomal dominant Thrombophilia due to protein C deficiency, autosomal recessive	Likely pathogenic (1)	criteria provided, single submitter	Nov 16, 2021	RCV002498834.1

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 08, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577736.4 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Comment: The R57W variant in the PROC gene has been reported previously in association with protein C deficiency (Zhou et al., 2003 [article in Chinese]; Stenson … (more) The R57W variant in the PROC gene has been reported previously in association with protein C deficiency (Zhou et al., 2003 [article in Chinese]; Stenson et al., 2014). The R57W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R57W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in association with protein C deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R57W variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
Pathogenic (Dec 12, 2023)	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: SCV000218832.10 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 7482420‚ 7792728‚ 8446940‚ 8499568‚ 14642106‚ 1464619‚ 1498334‚ 1771629‚ 8477066‚ 8505327 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 57 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 57 of the PROC protein (p.Arg57Trp). This variant is present in population databases (rs757583846, gnomAD 0.006%). This missense change has been observed in individual(s) with protein C deficiency (PMID: 7482420, 7792728, 8446940, 8499568, 14642106). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1432C>T, Arg15Trp, and C5498T. ClinVar contains an entry for this variant (Variation ID: 188230). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg57 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1464619, 1498334, 1771629, 8477066, 8505327). 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)
Likely pathogenic (Nov 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombophilia due to protein C deficiency, autosomal dominant Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579673.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PM2_SUP, PP1, PP3	Number of individuals with the variant: 1 Sex: male
Likely pathogenic (Nov 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombophilia due to protein C deficiency, autosomal dominant Thrombophilia due to protein C deficiency, autosomal recessive Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813713.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022

Comment:

The R57W variant in the PROC gene has been reported previously in association with protein C deficiency (Zhou et al., 2003 [article in Chinese]; Stenson et al., 2014). The R57W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R57W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in association with protein C deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R57W variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 57 of the PROC protein (p.Arg57Trp). This variant is present in population databases (rs757583846, gnomAD 0.006%). This missense change has been observed in individual(s) with protein C deficiency (PMID: 7482420, 7792728, 8446940, 8499568, 14642106). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1432C>T, Arg15Trp, and C5498T. ClinVar contains an entry for this variant (Variation ID: 188230). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg57 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1464619, 1498334, 1771629, 8477066, 8505327). 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.

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
[Type I hereditary protein C deficiency due to C5498T mutation in protein C gene].	Zhou RF	Zhonghua yi xue za zhi	2003	PMID: 14642106
Six different point mutations in seven Danish families with symptomatic protein C deficiency.	Lind B	Thrombosis and haemostasis	1995	PMID: 7792728
Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH.	Reitsma PH	Thrombosis and haemostasis	1995	PMID: 7482420
The contributions of individual gamma-carboxyglutamic acid residues in the calcium-dependent binding of recombinant human protein C to acidic phospholipid vesicles.	Zhang L	The Journal of biological chemistry	1993	PMID: 8505327
A Gla domain mutation (Arg 15-->Trp) in the protein C (PROC) gene causing type 2 protein C deficiency and recurrent venous thrombosis.	Millar DS	Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis	1993	PMID: 8499568
An abnormal protein C (protein C Yonago) with an amino acid substitution of Gly for Arg-15 caused by a single base mutation of C to G in codon 57 (CGG-->GGG). Deteriorated calcium-dependent conformation of the gamma-carboxyglutamic acid domain relevant to a thrombotic tendency.	Mimuro J	International journal of hematology	1993	PMID: 8477066
Protein C deficiency: a database of mutations. For the Protein C & S Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.	Reitsma PH	Thrombosis and haemostasis	1993	PMID: 8446940
Role of individual gamma-carboxyglutamic acid residues of activated human protein C in defining its in vitro anticoagulant activity.	Zhang L	Blood	1992	PMID: 1498334
Influence of specific gamma-carboxyglutamic acid residues on the integrity of the calcium-dependent conformation of human protein C.	Zhang L	The Journal of biological chemistry	1992	PMID: 1464619
A new hereditary abnormal protein C (protein C Yonago) with a dysfunctional Gla-domain.	Iijima K	Thrombosis research	1991	PMID: 1771629

Text-mined citations for rs757583846 ...

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.169C>T (p.Arg57Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs757583846 ...