ClinVar Genomic variation as it relates to human health
NM_000313.4(PROS1):c.586A>G (p.Lys196Glu)
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_000313.4(PROS1):c.586A>G (p.Lys196Glu)
Variation ID: 13318 Accession: VCV000013318.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q11.1 3: 93905799 (GRCh38) [ NCBI UCSC ] 3: 93624643 (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 16, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000313.4:c.586A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000304.2:p.Lys196Glu missense NM_001314077.2:c.682A>G NP_001301006.1:p.Lys228Glu missense NC_000003.12:g.93905799T>C NC_000003.11:g.93624643T>C NG_009813.1:g.73292A>G LRG_572:g.73292A>G LRG_572t1:c.586A>G LRG_572p1:p.Lys196Glu P07225:p.Lys196Glu - Protein change
- K196E, K228E
- Other names
- K155E
- Canonical SPDI
- NC_000003.12:93905798:T:C
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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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0.00020 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PROS1 | - | - |
GRCh38 GRCh37 |
475 | 504 |
Conditions - Germline
Condition
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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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV000014246.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2023 | RCV001055823.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV003952355.1 |
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
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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
(Jan 01, 2017)
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criteria provided, single submitter
Method: research
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Protein S deficiency
Affected status: unknown
Allele origin:
germline
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Snyder Lab, Genetics Department, Stanford University
Accession: SCV000853093.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to protein S deficiency, autosomal recessive
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001220233.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 196 of the PROS1 protein … (more)
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 196 of the PROS1 protein (p.Lys196Glu). This variant is present in population databases (rs121918474, gnomAD 0.03%). This missense change has been observed in individuals with conditions associated with reduce protein S deficiency including venous thromboembolism (VTE). Case-control studies have demonstrated that this is a common variant that is associated with increased risk of VTE in Japanese populations, though measurable protein S activity is not always reduced in these individuals and not all carriers are clinically affected (PMID: 10811787, 15978566, 16461766, 24233386, 27660039). This variant is also known as p.Lys155Glu and S-Tokushima. ClinVar contains an entry for this variant (Variation ID: 13318). 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 PROS1 protein function. Experimental studies have shown that this missense change affects PROS1 function (PMID: 16961608, 26251307, 30349894). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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PROS1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004779410.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PROS1 c.586A>G variant is predicted to result in the amino acid substitution p.Lys196Glu. This variant is alternatively referred to as p.Lys155Glu using legacy nomenclature. … (more)
The PROS1 c.586A>G variant is predicted to result in the amino acid substitution p.Lys196Glu. This variant is alternatively referred to as p.Lys155Glu using legacy nomenclature. This variant was reported in individuals with protein S deficiency and deep vein thrombosis (Hayashi et al. 1994. PubMed ID: 8298131; Miyata et al. 2008. PubMed ID: 18954896; Ikejiri et al. 2010. PubMed ID: 20811787). This variant is reported in 0.038% of alleles in individuals of East Asian descent in gnomAD. In vitro and In vivo experimental studies suggest this variant impacts protein function (Banno et al. 2015. PubMed ID: 26251307; Miyata et al. 2008. PubMed ID: 18954896). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to protein S deficiency, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000446549.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PROS1 c.586A>G (p.Lys196Glu) missense variant, commonly referred to as the protein S Tokushima variant, is well described in the literature and only found in … (more)
The PROS1 c.586A>G (p.Lys196Glu) missense variant, commonly referred to as the protein S Tokushima variant, is well described in the literature and only found in the Japanese population, where it has been shown to account for between nine and 30 percent of protein S abnormalities (Huang et al. 2016). Across a selection of the literature that studied 488 cases with protein S deficiency and thrombotic disease, the p.Lys196Glu variant is reported in a homozygous state in four affected individuals, in a compound heterozygous state in two affected individuals and one unaffected relative, and in a heterozygous state in 39 affected individuals, all of whom exhibited reduced protein S activity (Hayashi et al. 1994; Kimura et al. 2006a; Kimura et al. 2006b; Miyata et al. 2009; Yamanouchi et al. 2009; Ikejiri et al. 2010; Hayakawa et al. 2011). The p.Lys196Glu variant was detected in 103 out of 5751 controls and is reported at a frequency of 0.00046 in the East Asian population of the Exome Aggregation Consortium. Ikejiri et al. (2010) report the frequency of the variant is significantly higher in individuals with protein S deficiency and thrombotic disease compared to healthy individuals with odds ratios ranging from 4.99 to 8.56 for individuals being treated with warfarin in whom thrombotic disease has been resolved and individuals with thrombotic disease, respectively. Protein S activity in individuals carrying the p.Lys196Glu in a heterozygous state can range from being only slightly reduced to being nearly normal (Hayakawa et al. 2010). Banno et al. (2015) constructed a mouse model of the variant and demonstrated decreased protein C cofactor activity and increased susceptibility to venous thrombosis compared to wild type. Based on the collective evidence the p.Lys196Glu variant is classified as pathogenic for protein S deficiency and is considered to be a risk factor for thrombotic disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Feb 01, 1994)
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no assertion criteria provided
Method: literature only
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THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034494.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2015 |
Comment on evidence:
In a 29-year-old woman with thrombotic disease associated with heterozygous protein S deficiency (THPH5; 612336), Hayashi et al. (1994) identified a heterozygous A-to-G transition in … (more)
In a 29-year-old woman with thrombotic disease associated with heterozygous protein S deficiency (THPH5; 612336), Hayashi et al. (1994) identified a heterozygous A-to-G transition in exon 6 of the PROS1 gene, resulting in a lys155-to-glu (K155E) substitution in the second epidermal growth factor-like domain. The patient had normal levels of both total and free protein S antigen, but low cofactor activity for activated protein C, indicating that she had a variant of protein S, referred to as protein S Tokushima. Approximately one-half of the patient's protein S appeared to be the variant with a higher molecular weight than normal. The patient's mother and a maternal aunt also had thrombotic disease. The disorder in this family was classified as type IIb protein S deficiency. (less)
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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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Protein S K196E mutation reduces its cofactor activity for APC but not for TFPI. | Maruyama K | Research and practice in thrombosis and haemostasis | 2018 | PMID: 30349894 |
Recurrent Hemorrhagic Venous Infarctions Caused by Thrombosis of a Pontine Developmental Venous Anomaly and Protein S Mutation. | Nakamura Y | Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | 2016 | PMID: 27660039 |
Common genetic risk factors of venous thromboembolism in Western and Asian populations. | Huang SS | Genetics and molecular research : GMR | 2016 | PMID: 26985940 |
Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation. | Banno F | Blood | 2015 | PMID: 26251307 |
Dysfunction of protein C anticoagulant system, main genetic risk factor for venous thromboembolism in northeast Asians. | Yin T | Journal of thrombosis and thrombolysis | 2014 | PMID: 24233386 |
Genetic analysis of patients with deep vein thrombosis during pregnancy and postpartum. | Neki R | International journal of hematology | 2011 | PMID: 21811774 |
Mesenteric venous thrombosis in a child with type 2 protein S deficiency. | Hayakawa T | Journal of pediatric hematology/oncology | 2011 | PMID: 21285903 |
The association of protein S Tokushima-K196E with a risk of deep vein thrombosis. | Ikejiri M | International journal of hematology | 2010 | PMID: 20811787 |
Compound heterozygous mutations in the PROS1 gene responsible for quantitative and qualitative protein S deficiency. | Yamanouchi J | International journal of hematology | 2009 | PMID: 19826897 |
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 |
Plasma protein S activity correlates with protein S genotype but is not sensitive to identify K196E mutant carriers. | Kimura R | Journal of thrombosis and haemostasis : JTH | 2006 | PMID: 16961608 |
Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. | Kinoshita S | Clinical biochemistry | 2005 | PMID: 15978566 |
LEAFY and the evolution of rosette flowering in violet cress (Jonopsidium acaule, Brassicaceae). | Shu G | American journal of botany | 2000 | PMID: 10811787 |
Protein S Tokushima: abnormal molecule with a substitution of Glu for Lys-155 in the second epidermal growth factor-like domain of protein S. | Hayashi T | Blood | 1994 | PMID: 8298131 |
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Text-mined citations for rs121918474 ...
HelpRecord last updated Mar 17, 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.