NM_000488.4(SERPINC1):c.1247dup (p.Ser417fs) AND Hereditary antithrombin deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 20, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002463182.3

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1247dup (p.Ser417fs)]

NM_000488.4(SERPINC1):c.1247dup (p.Ser417fs)

Gene:

SERPINC1:serpin family C member 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1q25.1

Genomic location:

Preferred name:

NM_000488.4(SERPINC1):c.1247dup (p.Ser417fs)

Other names:

NM_000488.4(SERPINC1):c.1247dup; p.Ser417fs

HGVS:

NC_000001.11:g.173904037dup
NG_012462.1:g.18342dup
NM_000488.4:c.1247dupMANE SELECT
NM_001365052.2:c.1103dup
NM_001386302.1:c.1370dup
NM_001386303.1:c.1328dup
NM_001386304.1:c.1226dup
NM_001386305.1:c.1190dup
NM_001386306.1:c.1031dup
NP_000479.1:p.Ser417fs
NP_001351981.1:p.Ser369fs
NP_001373231.1:p.Ser458fs
NP_001373232.1:p.Ser444fs
NP_001373233.1:p.Ser410fs
NP_001373234.1:p.Ser398fs
NP_001373235.1:p.Ser345fs
LRG_577t1:c.1247dup
LRG_577:g.18342dup
NC_000001.10:g.173873175dup
NM_000488.3:c.1247dupC

Protein change:

S345fs

Links:

dbSNP: rs2526543302

Molecular consequence:

NM_000488.4:c.1247dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365052.2:c.1103dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386302.1:c.1370dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386303.1:c.1328dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386304.1:c.1226dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386305.1:c.1190dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386306.1:c.1031dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hereditary antithrombin deficiency (AT3D)
Synonyms:: Antithrombin III deficiency; Thrombophilia due to antithrombin III deficiency; Reduced antithrombin III activity; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013144; MedGen: C0272375; OMIM: 613118; Human Phenotype Ontology: HP:0001976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002520629	Laboratory for Immunogenetics and Molecular Haemostaseology, Universitaetsklinikum Erlangen	no assertion criteria provided	Likely pathogenic (Apr 14, 2022)	inherited	clinical testing
SCV005442764	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Uncertain Significance (Dec 20, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002520629

Laboratory for Immunogenetics and Molecular Haemostaseology, Universitaetsklinikum Erlangen

no assertion criteria provided

Likely pathogenic
(Apr 14, 2022)

inherited

clinical testing

SCV005442764

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Uncertain Significance
(Dec 20, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	inherited	yes	2	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Laboratory for Immunogenetics and Molecular Haemostaseology, Universitaetsklinikum Erlangen, SCV002520629.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	not provided
2		1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	inherited	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005442764.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1247dup (p.Ser417LysfsTer?) variant in SERPINC1 is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been reported in at least one family meeting an antithrombin activity level of < 0.8 IU/mL and a family history of the disease with reported antithrombin levels (PS4_Supporting; PMID: 38347553). More affected individuals without the details required for scoring were reported in ClinVar (SCV002520629.1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PVS1_moderate, PM2_supporting, PS4_supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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