ClinVar Genomic variation as it relates to human health
NM_000312.4(PROC):c.925G>A (p.Ala309Thr)
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
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NM_000312.4(PROC):c.925G>A (p.Ala309Thr)
Variation ID: 662 Accession: VCV000000662.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q14.3 2: 127428485 (GRCh38) [ NCBI UCSC ] 2: 128186061 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 21, 2015 Mar 23, 2024 May 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000312.4:c.925G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000303.1:p.Ala309Thr missense NM_001375602.1:c.1108G>A NP_001362531.1:p.Ala370Thr missense NM_001375603.1:c.1090G>A NP_001362532.1:p.Ala364Thr missense NM_001375604.1:c.988G>A NP_001362533.1:p.Ala330Thr missense NM_001375605.1:c.1027G>A NP_001362534.1:p.Ala343Thr missense NM_001375606.1:c.1093G>A NP_001362535.1:p.Ala365Thr missense NM_001375607.1:c.1111G>A NP_001362536.1:p.Ala371Thr missense NM_001375608.1:c.868G>A NP_001362537.1:p.Ala290Thr missense NM_001375609.1:c.901G>A NP_001362538.1:p.Ala301Thr missense NM_001375610.1:c.919G>A NP_001362539.1:p.Ala307Thr missense NM_001375611.1:c.925G>A NP_001362540.1:p.Ala309Thr missense NM_001375613.1:c.925G>A NP_001362542.1:p.Ala309Thr missense NC_000002.12:g.127428485G>A NC_000002.11:g.128186061G>A NG_016323.1:g.15066G>A LRG_599:g.15066G>A LRG_599t1:c.925G>A LRG_599p1:p.Ala309Thr P04070:p.Ala309Thr - Protein change
- A309T, A290T, A301T, A307T, A330T, A343T, A364T, A365T, A370T, A371T
- Other names
- A267T
- Canonical SPDI
- NC_000002.12:127428484:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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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. |
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PROC | - | - |
GRCh38 GRCh37 |
369 | 395 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Mar 21, 1992 | RCV000000697.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 6, 2022 | RCV000689442.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 26, 2017 | RCV003985071.1 |
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
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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. |
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Pathogenic
(May 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to protein C deficiency, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000817093.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This variant is also known as Ala267Thr. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change … (more)
This variant is also known as Ala267Thr. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PROC function (PMID: 20815936, 21901152). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 662). This missense change has been observed in individuals with protein C deficiency (PMID: 1347608, 17152060, 19535131, 28607330). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918146, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 309 of the PROC protein (p.Ala309Thr). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to protein C deficiency, autosomal dominant
Affected status: yes
Allele origin:
unknown
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500901.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation 1:
Clinical Features:
Pulmonary embolism (present) , low protein C (present)
Observation 2:
Clinical Features:
Pulmonary embolism (present) , low protein C (present)
Observation 3:
Clinical Features:
Pulmonary embolism (present) , low protein C (present)
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Pathogenic
(Jun 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary thrombophilia due to congenital protein C deficiency
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004801534.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The PROC c.925G>A (p.Ala309Thr) variant, also known as p.Ala267Thr, has been reported in at least four studies in 13 individuals with protein C deficiency including … (more)
The PROC c.925G>A (p.Ala309Thr) variant, also known as p.Ala267Thr, has been reported in at least four studies in 13 individuals with protein C deficiency including six individuals in a homozygous state (of which five are related) and one individual in a compound heterozygous state (Conard et al. 1992; Gandrille et al. 1995; Loop et al. 2004; Tjeldhorn et al. 2010a). In the family reported by Tjeldhorn et al. (2010a), the patient developed deep vein thrombosis in her leg at the age of 16 and skin necrosis after warfarin use, while her four family members homozygous for the variant did not have evidence of venous thrombosis but did have significantly reduced protein C activity and antigen in plasma. Several reported patients experienced episodes of skin necrosis following treatments with anticoagulants (Conard et al. 1992; Loop et al. 2004; Tjeldhorn et al. 2010a). The p.Ala309Thr variant was reported in a heterozygous state in six individuals from three families, including four individuals with no overt clinical symptoms but reduced protein C activity and one individual described as symptomatic but with no further clinical details provided. Reported individuals heterozygous for the p.Ala309Thr variant had a protein C activity ranging from 45 to 63 percent of normal, while individuals homozygous or compound heterozygous for the variant displayed more significant reduction, as low a three percent (Loop et al. 2004; Tjeldhorn et al. 2010a). Expression analysis in CHO and Huh7 cells found pAla309Thr demonstrated reduced intracellular levels, impaired secretion, and altered localization with inefficient transport compared to WT (Tjeldhorn et al. 2010b). A subsequent study by Tjeldhorn et al. found p.Ala309Thr to be associated with increased ER stress and unfolded protein response (UPR), which were associated with increased apoptotic activity in cells (Tjeldhorn et al. 2011). Using 4-phenylbutyrate (PBA) on CHO cells expressing p.Ala309Thr secretion was improved, localization was altered to the cytoplasm using the GRASP55 pathway (Chollet et al. 2015). The p.Ala309Thr variant was absent from 140 control chromosomes and is reported at a frequency of 0.000024 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the available evidence, the p.Ala309Thr variant is classified as pathogenic for protein C deficiency. (less)
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Pathogenic
(Mar 21, 1992)
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no assertion criteria provided
Method: literature only
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THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020847.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2015 |
Comment on evidence:
Conard et al. (1992) described a 57-year-old woman with autosomal recessive thrombophilia (THPH4; 612304) who had episodes of deep vein thrombosis at ages 45, 52, … (more)
Conard et al. (1992) described a 57-year-old woman with autosomal recessive thrombophilia (THPH4; 612304) who had episodes of deep vein thrombosis at ages 45, 52, and 54; each time she had skin necrosis at the start of anticoagulant treatment. Complete sequencing of the coding regions of the PROC gene showed homozygosity for an ala267-to-thr (A267T) substitution. She had been symptom-free until age 45 despite an appendectomy and 3 pregnancies. Her parents were cousins; her daughter, aged 31 years, was heterozygous for the mutation and remained symptom-free despite 2 pregnancies and 6 years of estrogen-progestagen treatment. (less)
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Pathogenic
(Oct 09, 2023)
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no assertion criteria provided
Method: clinical testing
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Thrombophilia due to protein C deficiency, autosomal dominant
Affected status: yes
Allele origin:
germline
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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041720.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
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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 |
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GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis. | Megy K | Journal of thrombosis and haemostasis : JTH | 2021 | PMID: 34355501 |
Genetic characterization of antithrombin, protein C, and protein S deficiencies in Polish patients. | Wypasek E | Polish archives of internal medicine | 2017 | PMID: 28607330 |
Protein C mutation (A267T) results in ER retention and unfolded protein response activation. | Tjeldhorn L | PloS one | 2011 | PMID: 21901152 |
Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport. | Tjeldhorn L | BMC cell biology | 2010 | PMID: 20815936 |
Hereditary protein C deficiency caused by the Ala267Thr mutation in the protein C gene is associated with symptomatic and asymptomatic venous thrombosis. | Tjeldhorn L | Thrombosis research | 2010 | PMID: 19535131 |
Identification and computationally-based structural interpretation of naturally occurring variants of human protein C. | Rovida E | Human mutation | 2007 | PMID: 17152060 |
Homozygous protein C deficiency with late onset and recurrent coumarin-induced skin necrosis. | Conard J | Lancet (London, England) | 1992 | PMID: 1347608 |
Text-mined citations for rs121918146 ...
HelpRecord last updated Mar 23, 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.