ClinVar Genomic variation as it relates to human health
NM_000312.4(PROC):c.574AAG[1] (p.Lys193del)
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.
Pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000312.4(PROC):c.574AAG[1] (p.Lys193del)
Variation ID: 225448 Accession: VCV000225448.16
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 2q14.3 2: 127426121-127426123 (GRCh38) [ NCBI UCSC ] 2: 128183697-128183699 (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 Dec 6, 2016 Jan 6, 2024 Nov 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000312.4:c.574AAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000303.1:p.Lys193del inframe deletion NM_000312.4:c.577_579delAAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000312.3:c.577_579delAAG NM_001375602.1:c.757AAG[1] NP_001362531.1:p.Lys254del inframe deletion NM_001375603.1:c.739AAG[1] NP_001362532.1:p.Lys248del inframe deletion NM_001375604.1:c.637AAG[1] NP_001362533.1:p.Lys214del inframe deletion NM_001375605.1:c.676AAG[1] NP_001362534.1:p.Lys227del inframe deletion NM_001375606.1:c.742AAG[1] NP_001362535.1:p.Lys249del inframe deletion NM_001375607.1:c.760AAG[1] NP_001362536.1:p.Lys255del inframe deletion NM_001375608.1:c.517AAG[1] NP_001362537.1:p.Lys174del inframe deletion NM_001375609.1:c.550AAG[1] NP_001362538.1:p.Lys185del inframe deletion NM_001375610.1:c.568AAG[1] NP_001362539.1:p.Lys191del inframe deletion NM_001375611.1:c.574AAG[1] NP_001362540.1:p.Lys193del inframe deletion NM_001375613.1:c.574AAG[1] NP_001362542.1:p.Lys193del inframe deletion NC_000002.12:g.127426123AAG[1] NC_000002.11:g.128183699AAG[1] NG_016323.1:g.12704AAG[1] LRG_599:g.12704AAG[1] LRG_599t1:c.577_579del - Protein change
- K193del, K174del, K185del, K191del, K214del, K227del, K248del, K249del, K254del, K255del
- Other names
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- Canonical SPDI
- NC_000002.12:127426120:AGAAGAAG:AGAAG
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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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0.00080 (AGAAG)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
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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 |
370 | 396 |
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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 13, 2021 | RCV000288890.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 3, 2023 | RCV003479063.1 |
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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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Thrombophilia due to protein C deficiency, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267464.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 4
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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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 C deficiency, autosomal dominant
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000416365.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PROC c.577_579delAAG (p.Lys193del) variant, which has several alternative names, has been well-described in the literature. The p.Lys193del variant is reported in at least seven … (more)
The PROC c.577_579delAAG (p.Lys193del) variant, which has several alternative names, has been well-described in the literature. The p.Lys193del variant is reported in at least seven studies in individuals with protein C deficiency and thrombotic disease in which it was found in 162 individuals, including two in a homozygous state (Miyata et al. 1998; Kinoshita et al. 2005; Tang et al. 2012; Tang et al. 2013; Iijima et al. 2010; Gu et al. 2014; Kim et al. 2014). In the same studies, the variant was detected in 69 out of 2,887 controls and is reported at a frequency of 0.00925 in the East Asian population of the Exome Aggregation Consortium. Tang et al. (2013) reported the frequency of the variant to be significantly higher in individuals with protein C deficiency and thrombotic disease compared to healthy individuals with an odds ratio of 2.84. The Lys193 residue is conserved among mammals. Protein C anticoagulant and amidolytic activities in individuals carrying the p.Lys193del variant in a heterozygous state can range from being only slightly reduced to being nearly normal (Iijima et al. 2010, Tang et al. 2012). Given the high prevalence of the variant in controls, the p.Lys193del variant is considered to be associated with incomplete penetrance. Not all individuals who carry this variant will demonstrate a reduction in levels of protein C activity. However, based on the strong association with disease and the combined evidence from the literature, the p.Lys193del variant is classified as pathogenic for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Jul 13, 2021)
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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: SCV001419976.2
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This variant, c.577_579del, results in the deletion of 1 amino acid(s) of the PROC protein (p.Lys193del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.577_579del, results in the deletion of 1 amino acid(s) of the PROC protein (p.Lys193del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs569796900, ExAC 0.9%). This variant has been observed in individual(s) with protein C deficiency as well as unaffected control individuals from East Asian populations. In a small case-control study including 1304 cases and 1334 controls from Chinese population, this variant was significantly associated with venous thrombosis (OR: 2.84, 95% CI 1.88-4.29). However, this needs further validation in a larger study (PMID: 9840027, 19822351, 21486865, 22817391, 23332921, 24028705, 24162787, 26250584). This variant is also known as Lys150del or c.574_576del (p.Lys192del). ClinVar contains an entry for this variant (Variation ID: 225448). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PROC protein function (PMID: 19822351, 21486865, 22817391, 23389250, 24028705, 24162787, 26250584). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223000.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PROC c.577_579delAAG (p.Lys193del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more)
Variant summary: PROC c.577_579delAAG (p.Lys193del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0007 in 251380 control chromosomes, predominantly at a frequency of 0.0096 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although this frequency is not suggestive of a variant associated with highly penetrant Mendelian disease. c.577_579delAAG has been reported in the literature as a risk factor for venous thrombosis and ischemic stroke, without a clear pattern of Mendelian inheritance, predominantly in individuals of East Asian descent (e.g., Tang_2012, Lu_2013). Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in a moderate reduction in anticoagulant activity relative to wild-type as well as a distinct transcriptional profile in HEK 293T cells (e.g., Tang_2012, Ding_2013, Lin_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23389250, 33896796, 22976599, 22817391). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as uncertain significance (n = 2) and pathogenic (n = 1). Based on the evidence outlined above, the variant likely represents a risk allele for venous thrombosis and ischemic stroke and was therefore classified as VUS-possibly pathogenic. (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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Supplementary research on K150del variant of activated protein C. | Lin WY | Aging | 2021 | PMID: 33896796 |
Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency. | Ichiyama M | Brain & development | 2016 | PMID: 26250584 |
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 |
Deficiency of antithrombin and protein C gene in 202 Chinese venous thromboembolism patients. | Gu Y | International journal of laboratory hematology | 2014 | PMID: 24028705 |
Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. | Ding Q | Thrombosis and haemostasis | 2013 | PMID: 23389250 |
Common genetic risk factors for venous thrombosis in the Chinese population. | Tang L | American journal of human genetics | 2013 | PMID: 23332921 |
Novel association of a PROC variant with ischemic stroke in a Chinese Han population. | Lu X | Human genetics | 2013 | PMID: 22976599 |
PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. | Tang L | Journal of thrombosis and haemostasis : JTH | 2012 | PMID: 22817391 |
Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group. | Zhu T | Haematologica | 2011 | PMID: 21486865 |
A homozygous protein C deficiency (Lys 192 del) who developed venous thrombosis for the first time at adulthood. | Iijima K | Thrombosis research | 2010 | PMID: 19822351 |
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 |
[Molecular mechanisms of protein C deficiency caused by C64W and F139V mutations]. | Zhou RF | Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | 2007 | PMID: 17649706 |
Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. | Kinoshita S | Clinical biochemistry | 2005 | PMID: 15978566 |
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 |
Genetic analysis of protein C deficiency in nineteen Japanese families: five recurrent defects can explain half of the deficiencies. | Miyata T | Thrombosis research | 1998 | PMID: 9840027 |
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Text-mined citations for rs199469469 ...
HelpRecord last updated May 19, 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.