The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature p.Leu99Phe, Antithrombin Budapest 3 (ATBp3)). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003516 (4/113752 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting (MAF =< 2.0 X 10-5 in gnomAD). The computational predictor REVEL gives a score of 0.853, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function (PP3). The variant has been reported to segregate with AT deficiency in at least 11 affected family members from 2 families (PP1_Strong; PMIDs: 32686144, 24072242). This variant has been reported in at least 100 probands with AT deficiency and is a founder variant in the Hugarian population. Further studies of the Hungarian cohort demonstrated that homozygosity was associated with thrombosis at a younger age and led to a high thrombotic risk while the heterozygous carriers also had venous and/or arterial thrombosis, as well as pregnancy complications. This variant was also reported in internal laboratory data (PS4_Very Strong; PMIDs: 26748602, 1555650, 32686144). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_strong, PP3, PS4_Very Strong
ClinVar Genomic variation as it relates to human health
NM_000488.4(SERPINC1):c.391C>T (p.Leu131Phe)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000488.4(SERPINC1):c.391C>T (p.Leu131Phe)
Variation ID: 18034 Accession: VCV000018034.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.1 1: 173914570 (GRCh38) [ NCBI UCSC ] 1: 173883708 (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 Sep 9, 2017 Feb 28, 2024 Sep 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000488.4:c.391C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000479.1:p.Leu131Phe missense NM_001365052.2:c.247C>T NP_001351981.1:p.Leu83Phe missense NM_001386302.1:c.391C>T NP_001373231.1:p.Leu131Phe missense NM_001386303.1:c.472C>T NP_001373232.1:p.Leu158Phe missense NM_001386304.1:c.391C>T NP_001373233.1:p.Leu131Phe missense NM_001386305.1:c.391C>T NP_001373234.1:p.Leu131Phe missense NM_001386306.1:c.391C>T NP_001373235.1:p.Leu131Phe missense NC_000001.11:g.173914570G>A NC_000001.10:g.173883708G>A NG_012462.1:g.7809C>T LRG_577:g.7809C>T LRG_577t1:c.391C>T LRG_577p1:p.Leu131Phe P01008:p.Leu131Phe - Protein change
- L131F, L83F, L158F
- Other names
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L99F
NM_000488.3(SERPINC1):c.391C>T
- Canonical SPDI
- NC_000001.11:173914569: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.
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The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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. |
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| SERPINC1 | - | - |
GRCh38 GRCh37 |
375 | 434 | |
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 (8) |
reviewed by expert panel
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Sep 21, 2023 | RCV000019650.41 | |
| Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851769.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jun 17, 2021 | RCV001543498.3 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 21, 2023)
|
reviewed by expert panel
Method: curation
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Hereditary antithrombin deficiency
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Clingen Thrombosis Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004037391.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature … (more)
The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature p.Leu99Phe, Antithrombin Budapest 3 (ATBp3)). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003516 (4/113752 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting (MAF =< 2.0 X 10-5 in gnomAD). The computational predictor REVEL gives a score of 0.853, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function (PP3). The variant has been reported to segregate with AT deficiency in at least 11 affected family members from 2 families (PP1_Strong; PMIDs: 32686144, 24072242). This variant has been reported in at least 100 probands with AT deficiency and is a founder variant in the Hugarian population. Further studies of the Hungarian cohort demonstrated that homozygosity was associated with thrombosis at a younger age and led to a high thrombotic risk while the heterozygous carriers also had venous and/or arterial thrombosis, as well as pregnancy complications. This variant was also reported in internal laboratory data (PS4_Very Strong; PMIDs: 26748602, 1555650, 32686144). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_strong, PP3, PS4_Very Strong (less)
|
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Pathogenic
(Feb 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary antithrombin deficiency
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581438.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM3_STR, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Oct 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary antithrombin deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810528.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Aug 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary antithrombin deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001380298.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 131 of the SERPINC1 protein (p.Leu131Phe). This variant is present in population databases (rs121909567, gnomAD 0.004%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 22498748, 24072242, 24158114, 26748602). It has also been observed to segregate with disease in related individuals. This variant is also known as p.L99F. ClinVar contains an entry for this variant (Variation ID: 18034). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 1555650, 22498748, 29215785). (less)
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Likely pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary antithrombin deficiency
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899334.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1: Observation 2:
Sex: female
Ethnicity/Population group: European,South-Asian
Observation 3:
Sex: female
Ethnicity/Population group: South-Asian
Observation 4:
Sex: female
Ethnicity/Population group: European
Observation 5:
Sex: female
Ethnicity/Population group: Other
|
|
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Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: research
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Deep venous thrombosis
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899704.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Sex: male
Ethnicity/Population group: Other
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Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762107.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Global developmental delay (present) , Hereditary antithrombin deficiency (present) , Spastic hemiparesis (present) , Cognitive impairment (present)
Sex: male
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary antithrombin deficiency
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002515496.2
First in ClinVar: May 21, 2022 Last updated: Jul 22, 2023
Comment:
Submitted to GoldVariant by Kathleen Freson, Center for Molecular and Vascular Biology, Leuven, Belgium
|
Observation 1:
Clinical Features:
Thrombosis (present) , vena cava superior syndrome (present)
Observation 2:
Clinical Features:
Deep vein thrombosis (present)
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Pathogenic
(Apr 11, 1990)
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no assertion criteria provided
Method: literature only
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THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039948.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2017 |
Comment on evidence:
Olds et al. (1992) described a CTC-to-TTC transition at codon 99 of the AT3 gene, altering the normal leucine to phenylalanine. The proband had a … (more)
Olds et al. (1992) described a CTC-to-TTC transition at codon 99 of the AT3 gene, altering the normal leucine to phenylalanine. The proband had a history of venous thrombotic disease (613118) and was found to be homozygous for the mutation. The variant protein showed reduced heparin affinity and reduced antiproteinase activity in the presence of either unfractionated heparin or the AT-binding heparin pentasaccharide, when compared to normal AT. The substitution is located near the proposed heparin-binding site. (less)
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Pathogenic
(Oct 09, 2023)
|
no assertion criteria provided
Method: clinical testing
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Hereditary antithrombin deficiency
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041776.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 131 of the SERPINC1 protein (p.Leu131Phe). This variant is present in population databases (rs121909567, gnomAD 0.004%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 22498748, 24072242, 24158114, 26748602). It has also been observed to segregate with disease in related individuals. This variant is also known as p.L99F. ClinVar contains an entry for this variant (Variation ID: 18034). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 1555650, 22498748, 29215785).
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:
The c.391C>T (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 131 (p.Leu131Phe; legacy nomenclature p.Leu99Phe, Antithrombin Budapest 3 (ATBp3)). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003516 (4/113752 alleles) in the non-Finnish European population, which does not meet criteria for PM2_Supporting (MAF =< 2.0 X 10-5 in gnomAD). The computational predictor REVEL gives a score of 0.853, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function (PP3). The variant has been reported to segregate with AT deficiency in at least 11 affected family members from 2 families (PP1_Strong; PMIDs: 32686144, 24072242). This variant has been reported in at least 100 probands with AT deficiency and is a founder variant in the Hugarian population. Further studies of the Hungarian cohort demonstrated that homozygosity was associated with thrombosis at a younger age and led to a high thrombotic risk while the heterozygous carriers also had venous and/or arterial thrombosis, as well as pregnancy complications. This variant was also reported in internal laboratory data (PS4_Very Strong; PMIDs: 26748602, 1555650, 32686144). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_strong, PP3, PS4_Very Strong
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 131 of the SERPINC1 protein (p.Leu131Phe). This variant is present in population databases (rs121909567, gnomAD 0.004%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 22498748, 24072242, 24158114, 26748602). It has also been observed to segregate with disease in related individuals. This variant is also known as p.L99F. ClinVar contains an entry for this variant (Variation ID: 18034). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 1555650, 22498748, 29215785).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
| Expression and functional characterization of two natural heparin-binding site variants of antithrombin. | Dinarvand P | Journal of thrombosis and haemostasis : JTH | 2018 | PMID: 29215785 |
| Founder effect is responsible for the p.Leu131Phe heparin-binding-site antithrombin mutation common in Hungary: phenotype analysis in a large cohort. | Gindele R | Journal of thrombosis and haemostasis : JTH | 2016 | PMID: 26748602 |
| A new case of successful outcome of pregnancy in a carrier of homozygous type II (L99F) antithrombin deficiency. | Pascual C | Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis | 2014 | PMID: 24158114 |
| Homozygous antithrombin deficiency in adolescents presenting with lower extremity thrombosis and renal complications: two case reports from Turkey. | Sarper N | Journal of pediatric hematology/oncology | 2014 | PMID: 24072242 |
| Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism. | Martínez-Martínez I | Blood | 2012 | PMID: 22498748 |
| Antithrombin Budapest 3. An antithrombin variant with reduced heparin affinity resulting from the substitution L99F. | Olds RJ | FEBS letters | 1992 | PMID: 1555650 |
| Antithrombin III Padua 2: a single base substitution in exon 2 detected with PCR and direct genomic sequencing. | Olds RJ | Nucleic acids research | 1990 | PMID: 2336381 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/79c443a1-cbfc-43e9-8bed-9b6b5bc302be | - | - | - | - |
Text-mined citations for rs121909567 ...
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 08, 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.