VCV000018011.82 - ClinVar

NM_000488.4(SERPINC1):c.218C>T (p.Pro73Leu)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Hereditary antithrombin deficiency

Classification is based on the expert panel submission

Sep 2023 by Clingen Thrombosis Variant Curation Expert Panel, ClinGen

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000488.4(SERPINC1):c.218C>T (p.Pro73Leu)

Variation ID: 18011 Accession: VCV000018011.82

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q25.1 1: 173914743 (GRCh38) [ NCBI UCSC ] 1: 173883881 (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	Dec 6, 2014	Jun 20, 2026	Sep 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000488.4:c.218C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000479.1:p.Pro73Leu	missense
NM_001365052.2:c.74C>T	NP_001351981.1:p.Pro25Leu	missense
NM_001386302.1:c.218C>T	NP_001373231.1:p.Pro73Leu	missense
NM_001386303.1:c.299C>T	NP_001373232.1:p.Pro100Leu	missense
NM_001386304.1:c.218C>T	NP_001373233.1:p.Pro73Leu	missense
NM_001386305.1:c.218C>T	NP_001373234.1:p.Pro73Leu	missense
NM_001386306.1:c.218C>T	NP_001373235.1:p.Pro73Leu	missense
NC_000001.11:g.173914743G>A
NC_000001.10:g.173883881G>A
NG_012462.1:g.7636C>T
LRG_577:g.7636C>T
LRG_577t1:c.218C>T	LRG_577p1:p.Pro73Leu
	P01008:p.Pro73Leu

... more HGVS ... less HGVS

Protein change

P73L, P25L, P100L

Other names

P41L
NM_000488.3(SERPINC1):c.218C>T

Canonical SPDI

NC_000001.11:173914742:G:A

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00043

Exome Aggregation Consortium (ExAC) 0.00072

The Genome Aggregation Database (gnomAD), exomes 0.00082

The Genome Aggregation Database (gnomAD) 0.00084

The Genome Aggregation Database (gnomAD) 0.00092

Links

ClinGen: CA210756 UniProtKB: P01008#VAR_007036 OMIM: 107300.0012 dbSNP: rs121909551 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.
SERPINC1		-	-	GRCh38 GRCh37	478	539

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.
Hereditary antithrombin deficiency	Pathogenic (19)	reviewed by expert panel	Sep 21, 2023	RCV000019627.76
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Nov 14, 2025	RCV001090508.52

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.	Expand all rows Collapse all rows 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.
Pathogenic (Sep 21, 2023) C Contributing to aggregate classification	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Hereditary antithrombin deficiency (Autosomal dominant inheritance)	Clingen Thrombosis Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV004037387.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b7a99380-d40e-4611-81d1-d60401803a33 Comment: show The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. 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: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Sep 30, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Hereditary antithrombin deficiency	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001983481.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Publications: PubMed (6) PubMed: 22498748‚ 23910795‚ 27322195‚ 2794060‚ 3080419‚ 33614741 Comment: show Variant summary: SERPINC1 c.218C>T (p.Pro73Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 251456 control chromosomes, predominatly in the Finnish and non-Finnish European subpopulations with a frequency of 0.0044 and 0.00089 respectively. The variant, c.218C>T (aka. Pro41Leu or AT Basel), is well known variant in the literature and has been reported in numerous individuals affected with Antithrombin III Deficiency (e.g. Chang_1986 , Molho-Sabatier_1989, Puurunen_2013, Bereczky_2021), and is considered to be a founder variant in the Finnish population (Puurunen_2013). Several of these publications reported significantly reduced antithrombin activity in carriers. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated reduced heparin binding properties (Martinez-Martinez_2012, Bohdan_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 22, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	Fulgent Genetics, Fulgent Genetics Accession: SCV002810338.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Apr 12, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV003925554.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023 Comment: PMID:25741868 (PS4, PP3, PS3)	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002515499.3 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: 2 Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: thrombosis (present) Comment on clinical features: low antithrombin levels Zygosity: 1 Single Heterozygote Platform type: WES Observation 2 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: thrombosis (present) Comment on clinical features: low antithrombin levels Zygosity: 1 Single Heterozygote Platform Type: WES

Pathogenic (May 27, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198210.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 03, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005914896.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Likely pathogenic (Feb 21, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	Revvity Omics, Revvity Accession: SCV002019179.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely Pathogenic (Jun 19, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Hereditary antithrombin deficiency (Autosomal dominant inheritance)	Variantyx, Inc. Accession: SCV007520039.1 First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026	Publications: PubMed (1) PubMed: 28300866 Comment: show This is a nonsynonymous variant in the SERPINC1 gene (OMIM: 107300). Pathogenic variants in this gene have been associated with autosomal dominant thrombophilia 7 due to antithrombin III deficiency. This is an established founder variant in the Finnish population (PMID: 23910795) (PS4). It lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the SERPINC1 protein (PM1). Multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.658) (PP3). This variant has a 0.1086% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as likely pathogenic for autosomal dominant thrombophilia 7 due to antithrombin III deficiency. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Mar 26, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency (Autosomal recessive inheritance)	First Genomix Gene Laboratory, Genetic Diagnostics Department Accession: SCV007580777.1 First in ClinVar: May 03, 2026 Last updated: May 03, 2026	Comment: show As part of Carrier Screening testing performed at First Genomix, this variant was identified in a heterozygous state in a patient who is not affected with this condition. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1

Pathogenic (Apr 27, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Hereditary antithrombin deficiency	Illumina Laboratory Services, Illumina Accession: SCV000351487.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (5) PubMed: 23910795‚ 24956267‚ 27322195‚ 2794060‚ 3080419 Comment: show The SERPINC1 c.218C>T (p.Pro73Leu) missense variant is well described in the literature. Across a selection of the available literature, the p.Pro73Leu variant, which is also referred to as p.Pro41Leu, has been identified in a heterozygous state in four individuals diagnosed with antithrombin-III deficiency and with unspecified zygosity in 96 affected individuals (Chang et al. 1986; Molho-Sabatier et al. 1989; Puurunen et al. 2013; Feddersen et al. 2014). The p.Pro41Leu variant was absent from 106 controls, but is reported at a frequency of 0.00408 in the European (Finnish) population of the Exome Aggregation Consortium. Puurunen et al. (2013) suggest that the p.Pro73Leu variant is a founder variant in the Finnish population associated with type II hereditary antithrombin deficiency. The Pro73 residue is located at a heparin binding site. Bohdan et al. (2016) conducted a functional study to evaluate the effect of the p.Pro73Leu variant on binding affinity. The binding affinity between heparanase and antithrombin was greatly reduced in HEK-EBNA cells transfected with p.Pro73Leu variant plasmids compared to wildtype. Based on the collective evidence, the p.Pro73Leu variant is classified as pathogenic for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Feb 01, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899323.2 First in ClinVar: Sep 29, 2019 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 31064749 Observation: 2 Observation 1 Collection method: research Allele origin: unknown Affected status: yes Zygosity: 1 Single Heterozygote Sex: female Ethnicity/Population group: European Platform type: Targeted sequencing Observation 2 Collection method: research Allele origin: unknown Affected status: yes Zygosity: 1 Single Heterozygote Sex: female Ethnicity/Population group: European Platform Type: Targeted sequencing

Pathogenic (Sep 02, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency (Autosomal dominant inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368365.2 First in ClinVar: Oct 13, 2024 Last updated: Apr 13, 2025	Comment: show Criteria applied: PS4_VSTR,PP1_STR,PM1,PP3,PP4 (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Venous thrombosis (present) , Autoimmunity (present) , Recurrent tonsillitis (present) , Immunodeficiency (present) , Elevated circulating hepatic transaminase concentration (present) , Recurrent infections (present) , Pulmonic stenosis (present) , Recurrent fever (present) Sex: male

Likely pathogenic (Nov 14, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001820746.4 First in ClinVar: Sep 08, 2021 Last updated: Nov 22, 2025	Comment: show Published functional studies demonstrate defects in heparin binding properties (PMID: 22498748, 27322195); Reported previously as P41L or AT Basel using alternate nomenclature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24196373, 24956267, 26748602, 31064749, 22498748, 25637381, 3080419, 28317092, 2794060, 23910795, 27322195, 24082793, 29902631, 28300866, 30721820, 25837307, 34426522, 31589614, 33614741, 36764659, 34653293, 33917853, 34800304, 37201530) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 21, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002573725.3 First in ClinVar: Sep 24, 2022 Last updated: Jan 11, 2026	Publications: PubMed (19) PubMed: 2012760‚ 2372510‚ 23910795‚ 24082793‚ 24196373‚ 24956267‚ 25466846‚ 25837307‚ 2615648‚ 26748602‚ 2794060‚ 28300866‚ 29153735‚ 30721820‚ 33917853‚ 34800304‚ 37201530‚ 7455996‚ 7734360 Comment: show PP1_strong, PP3, PP4, PP5, PM1, PS4_very_strong (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 10

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (IMAGENE.ME Variant Classification SOP 2022)	Hereditary antithrombin deficiency	Imagene.me medical diagnostic laboratory, IMAGENE.ME SA Accession: SCV007329868.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Comment: show Classified according to the IMAGENE.ME variant classification SOP based on the ACMG guidelines as Pathogenic (P): PS4_VeryStrong + PP1_Strong + PM1 + PP3 + PP4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 01, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hereditary antithrombin deficiency	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000756581.9 First in ClinVar: Sep 09, 2017 Last updated: Feb 23, 2026	Publications: PubMed (9) PubMed: 23910795‚ 24082793‚ 24956267‚ 26748602‚ 27322195‚ 2794060‚ 28317092‚ 28492532‚ 3080419 Comment: show This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the SERPINC1 protein (p.Pro73Leu). This variant is present in population databases (rs121909551, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with type II antithrombin deficiency (PMID: 2794060, 3080419, 23910795, 24082793, 24956267, 26748602, 28317092). It is commonly reported in individuals of Finnish ancestry (PMID: 2794060, 3080419, 23910795, 24082793, 24956267, 26748602, 28317092). This variant is also known as Pro41Leu or AT Basel. ClinVar contains an entry for this variant (Variation ID: 18011). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SERPINC1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 2794060, 3080419, 24082793, 27322195). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 05, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	Mendelics Accession: SCV007519267.1 First in ClinVar: Mar 21, 2026 Last updated: Mar 21, 2026	Comment: show Likely pathogenic/Pathogenic according to ACMG criteria. Variant from clinical tested patient. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Feb 16, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary antithrombin deficiency	Clinical Genomic Analysis (GENYSIS) Core, University of North Carolina at Chapel Hill Study: UNC Genetic Determinants of Neurological and Developmental Disorders (GDNDD) Study Accession: SCV007595752.1 First in ClinVar: May 16, 2026 Last updated: May 16, 2026	Publications: PubMed (1) PubMed: 30005274 Comment: show SERPINC1 c.218C>T, p.(Pro73Leu), is a missense variant predicted to alter a single amino acid in the encoded protein from a proline to a leucine and has been associated with moderate type II heparin binding site (HBS) AT deficiency (PMID:30005274). As this variant occurs at an HBS, has been reported in at least 35 probands with AT deficiency, with 17 segregations seen across 35 families, and is predicted by in silico models to have a damaging effect on the protein, the ClinGen Thrombosis Variant Curation Expert Panel have classified it as pathogenic. (less) Observation: 1 Collection method: research Allele origin: maternal Affected status: unknown more Observation 1 Collection method: research Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Clinical Features: Typical absence seizure (present) , Delayed speech and language development (present) Zygosity: 1 Single Heterozygote Secondary finding: yes Method: This variant was identified by research next-generation sequencing and clinically confirmed by Sanger sequencing in the UNC Molecular Genetics Laboratory, UNC-Chapel Hill

Pathogenic (Jul 31, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (DASA Assertion Criteria)	not provided	Dasa Accession: SCV007598995.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Publications: PubMed (8) PubMed: 23910795‚ 24082793‚ 24956267‚ 26748602‚ 2794060‚ 28300866‚ 28317092‚ 3080419 Comment: show NM_000488.4(SERPINC1):c.218C>T (p.Pro73Leu) is a missense variant that results in the substitution of proline with leucine. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 2794060; PMID: 3080419; PMID: 23910795; PMID: 24082793; PMID: 24956267). This variant has been recurrently observed in individuals with related phenotype (PMID: 2794060; PMID: 3080419; PMID: 23910795; PMID: 24082793; PMID: 24956267). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 01, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246102.38 First in ClinVar: May 12, 2020 Last updated: Jun 20, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 2

Pathogenic (Oct 30, 2023) N Not contributing to aggregate classification	no assertion criteria provided	Hereditary antithrombin deficiency	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004099345.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Mar 01, 1992) N Not contributing to aggregate classification	Flagged submission flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Source: ClinGen	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE	OMIM Accession: SCV000039925.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2017	Publications: PubMed (6) PubMed: 1536946‚ 2372510‚ 2615648‚ 2794060‚ 3080419‚ 3663508 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: This variant, formerly titled THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY, has been reclassified because its contribution to the phenotype has not been confirmed. AT-III Clichy, … (more) This variant, formerly titled THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY, has been reclassified because its contribution to the phenotype has not been confirmed. AT-III Clichy, a substitution of leucine for proline-41, was described by Chang and Tran (1986), Aiach et al. (1987), and Molho-Sabatier et al. (1989). The variant has also been called AT-III Clichy-2, AT-III Basel, AT-III Franconville. Aiach et al. (1987) found the mutation in heterozygous state in a 24-year-old woman presenting with a thoracic outlet syndrome. Perry and Carrell (1989) described the same substitution in this heparin-binding mutation, which was caused by a CGT-to-CAT change in exon 2. Olds et al. (1990) noted that this mutation occurs within a CG dinucleotide, a recognized hotspot for single base mutations. In a woman referred for routine prepregnancy testing and in several members of her family, de Roux et al. (1990) found heterozygosity for the pro41-to-leu mutation. None had had thrombotic complications. Testing of the properties of the mutant AT-III suggested that proline-41 is more involved in the molecular changes induced by heparin than in the primary binding of the activator. (less)

Likely benign (Jun 01, 2014) N Not contributing to aggregate classification	Flagged submission flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Source: ClinGen	Antithrombin deficiency (Autosomal dominant inheritance)	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190626.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

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Comment:

The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. 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: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4.

Comment:

Variant summary: SERPINC1 c.218C>T (p.Pro73Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 251456 control chromosomes, predominatly in the Finnish and non-Finnish European subpopulations with a frequency of 0.0044 and 0.00089 respectively. The variant, c.218C>T (aka. Pro41Leu or AT Basel), is well known variant in the literature and has been reported in numerous individuals affected with Antithrombin III Deficiency (e.g. Chang_1986 , Molho-Sabatier_1989, Puurunen_2013, Bereczky_2021), and is considered to be a founder variant in the Finnish population (Puurunen_2013). Several of these publications reported significantly reduced antithrombin activity in carriers. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated reduced heparin binding properties (Martinez-Martinez_2012, Bohdan_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This is a nonsynonymous variant in the SERPINC1 gene (OMIM: 107300). Pathogenic variants in this gene have been associated with autosomal dominant thrombophilia 7 due to antithrombin III deficiency. This is an established founder variant in the Finnish population (PMID: 23910795) (PS4). It lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the SERPINC1 protein (PM1). Multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.658) (PP3). This variant has a 0.1086% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as likely pathogenic for autosomal dominant thrombophilia 7 due to antithrombin III deficiency.

Comment:

The SERPINC1 c.218C>T (p.Pro73Leu) missense variant is well described in the literature. Across a selection of the available literature, the p.Pro73Leu variant, which is also referred to as p.Pro41Leu, has been identified in a heterozygous state in four individuals diagnosed with antithrombin-III deficiency and with unspecified zygosity in 96 affected individuals (Chang et al. 1986; Molho-Sabatier et al. 1989; Puurunen et al. 2013; Feddersen et al. 2014). The p.Pro41Leu variant was absent from 106 controls, but is reported at a frequency of 0.00408 in the European (Finnish) population of the Exome Aggregation Consortium. Puurunen et al. (2013) suggest that the p.Pro73Leu variant is a founder variant in the Finnish population associated with type II hereditary antithrombin deficiency. The Pro73 residue is located at a heparin binding site. Bohdan et al. (2016) conducted a functional study to evaluate the effect of the p.Pro73Leu variant on binding affinity. The binding affinity between heparanase and antithrombin was greatly reduced in HEK-EBNA cells transfected with p.Pro73Leu variant plasmids compared to wildtype. Based on the collective evidence, the p.Pro73Leu variant is classified as pathogenic for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Published functional studies demonstrate defects in heparin binding properties (PMID: 22498748, 27322195); Reported previously as P41L or AT Basel using alternate nomenclature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24196373, 24956267, 26748602, 31064749, 22498748, 25637381, 3080419, 28317092, 2794060, 23910795, 27322195, 24082793, 29902631, 28300866, 30721820, 25837307, 34426522, 31589614, 33614741, 36764659, 34653293, 33917853, 34800304, 37201530)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the SERPINC1 protein (p.Pro73Leu). This variant is present in population databases (rs121909551, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with type II antithrombin deficiency (PMID: 2794060, 3080419, 23910795, 24082793, 24956267, 26748602, 28317092). It is commonly reported in individuals of Finnish ancestry (PMID: 2794060, 3080419, 23910795, 24082793, 24956267, 26748602, 28317092). This variant is also known as Pro41Leu or AT Basel. ClinVar contains an entry for this variant (Variation ID: 18011). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SERPINC1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 2794060, 3080419, 24082793, 27322195). For these reasons, this variant has been classified as Pathogenic.

Comment:

SERPINC1 c.218C>T, p.(Pro73Leu), is a missense variant predicted to alter a single amino acid in the encoded protein from a proline to a leucine and has been associated with moderate type II heparin binding site (HBS) AT deficiency (PMID:30005274). As this variant occurs at an HBS, has been reported in at least 35 probands with AT deficiency, with 17 segregations seen across 35 families, and is predicted by in silico models to have a damaging effect on the protein, the ClinGen Thrombosis Variant Curation Expert Panel have classified it as pathogenic.

Comment:

NM_000488.4(SERPINC1):c.218C>T (p.Pro73Leu) is a missense variant that results in the substitution of proline with leucine. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 2794060; PMID: 3080419; PMID: 23910795; PMID: 24082793; PMID: 24956267). This variant has been recurrently observed in individuals with related phenotype (PMID: 2794060; PMID: 3080419; PMID: 23910795; PMID: 24082793; PMID: 24956267). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Antithrombin Deficiency Is Associated with Prothrombotic Plasma Fibrin Clot Phenotype.	Natorska J	Thrombosis and haemostasis	2023	PMID: 37201530
Molecular and clinical characterization of transient antithrombin deficiency: A new concept in congenital thrombophilia.	Bravo-Pérez C	American journal of hematology	2022	PMID: 34800304
Investigation of the Differences in Antithrombin to Heparin Binding among Antithrombin Budapest 3, Basel, and Padua Mutations by Biochemical and In Silico Methods.	Gindele R	Biomolecules	2021	PMID: 33917853
Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases.	Bereczky Z	Frontiers in cardiovascular medicine	2021	PMID: 33614741
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
SERPINC1 variants causing hereditary antithrombin deficiency in a Danish population.	Kjaergaard AD	Thrombosis research	2019	PMID: 30721820
The genetics of antithrombin.	Corral J	Thrombosis research	2018	PMID: 30005274
Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center.	Gindele R	Thrombosis research	2017	PMID: 29153735
SERPINC1 gene mutations in antithrombin deficiency.	Mulder R	British journal of haematology	2017	PMID: 28317092
Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited deficiency.	Alhenc-Gelas M	Thrombosis and haemostasis	2017	PMID: 28300866
Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site.	Bohdan N	PloS one	2016	PMID: 27322195
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
Antithrombin heparin binding site deficiency: A challenging diagnosis of a not so benign thrombophilia.	Orlando C	Thrombosis research	2015	PMID: 25837307
Development of a novel, rapid assay for detection of heparin-binding defect antithrombin deficiencies: the heparin-antithrombin binding (HAB) ratio.	Moore GW	Thrombosis research	2015	PMID: 25466846
Discordant diagnoses obtained by different approaches in antithrombin mutation analysis.	Feddersen S	Clinical biochemistry	2014	PMID: 24956267
Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency.	Luxembourg B	Thrombosis and haemostasis	2014	PMID: 24196373
Use of recombinant human antithrombin concentrate in pregnancy.	Kreuziger LM	International journal of women's health	2013	PMID: 24082793
Type II antithrombin deficiency caused by a founder mutation Pro73Leu in the Finnish population: clinical picture.	Puurunen M	Journal of thrombosis and haemostasis : JTH	2013	PMID: 23910795
Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism.	Martínez-Martínez I	Blood	2012	PMID: 22498748
Antithrombins Southport (Leu 99 to Val) and Vienna (Gln 118 to Pro): two novel antithrombin variants with abnormal heparin binding.	Chowdhury V	British journal of haematology	1995	PMID: 7734360
Antithrombin III Budapest: a single amino acid substitution (429Pro to Leu) in a region highly conserved in the serpin family.	Olds RJ	Blood	1992	PMID: 1536946
The incidence of dysfunctional antithrombin variants: four cases in 210 patients with thromboembolic disease.	Harper PL	British journal of haematology	1991	PMID: 2012760
Clinical and biochemical characterization of antithrombin III Franconville, a variant with Pro 41 Leu mutation.	de Roux N	British journal of haematology	1990	PMID: 2372510
Molecular characterization of antithrombin III (ATIII) variants using polymerase chain reaction. Identification of the ATIII Charleville as an Ala 384 Pro mutation.	Molho-Sabatier P	The Journal of clinical investigation	1989	PMID: 2794060
CpG dinucleotides are "hotspots" for mutation in the antithrombin III gene. Twelve variants identified using the polymerase chain reaction.	Perry DJ	Molecular biology & medicine	1989	PMID: 2615648
An abnormal antithrombin III (AT III) with low heparin affinity: AT III Clichy.	Aiach M	British journal of haematology	1987	PMID: 3663508
Antithrombin III Basel. Identification of a Pro-Leu substitution in a hereditary abnormal antithrombin with impaired heparin cofactor activity.	Chang JY	The Journal of biological chemistry	1986	PMID: 3080419
Purification and partial characterization of a hereditary abnormal antithrombin III fraction of a patient with recurrent thrombophlebitis.	Tran TH	Thrombosis and haemostasis	1980	PMID: 7455996
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b7a99380-d40e-4611-81d1-d60401803a33	-	-	-	-
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Text-mined citations for rs121909551 ...

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 Jun 20, 2026