NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr) AND Hereditary antithrombin deficiency

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 16, 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:: RCV000019619.32

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr)]

NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.1

Genomic location:

Preferred name:

NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr)

Other names:

A404T; NM_000488.4(SERPINC1):c.1306G>A

HGVS:

NC_000001.11:g.173903978C>T
NG_012462.1:g.18401G>A
NM_000488.4:c.1306G>AMANE SELECT
NM_001365052.2:c.1162G>A
NM_001386302.1:c.1429G>A
NM_001386303.1:c.1387G>A
NM_001386304.1:c.1285G>A
NM_001386305.1:c.1249G>A
NM_001386306.1:c.1090G>A
NP_000479.1:p.Ala436Thr
NP_000479.1:p.Ala436Thr
NP_001351981.1:p.Ala388Thr
NP_001373231.1:p.Ala477Thr
NP_001373232.1:p.Ala463Thr
NP_001373233.1:p.Ala429Thr
NP_001373234.1:p.Ala417Thr
NP_001373235.1:p.Ala364Thr
LRG_577t1:c.1306G>A
LRG_577:g.18401G>A
LRG_577p1:p.Ala436Thr
NC_000001.10:g.173873116C>T
NM_000488.3:c.1306G>A
P01008:p.Ala436Thr

Protein change:

A364T; ALA404THR

Links:

UniProtKB: P01008#VAR_007081; OMIM: 107300.0001; dbSNP: rs121909546

NCBI 1000 Genomes Browser:

rs121909546

Molecular consequence:

NM_000488.4:c.1306G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1429G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1387G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1285G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1249G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1090G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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RecName: Full=Small ribosomal subunit protein uS15m; AltName: Full=28S ribosomal...
RecName: Full=Small ribosomal subunit protein uS15m; AltName: Full=28S ribosomal protein S15, mitochondrial; Short=MRP-S15; Short=S15mt; Flags: Precursor
gi|82183063|sp|Q6DGL8.1|RT15_DANRE

Protein
GLT8D1 [Nomascus leucogenys]
GLT8D1 [Nomascus leucogenys]
Gene ID:100583782

Gene
Rubella Syndrome, Congenital
Rubella Syndrome, Congenital
Transplacental infection of the fetus with rubella usually in the first trimester of pregnancy, as a consequence of maternal infection, resulting in various developmental abno...<br/>Year introduced: 1991(1987)

MeSH
LOC795056 [Danio rerio]
LOC795056 [Danio rerio]
Gene ID:795056

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039917	OMIM	no assertion criteria provided	Pathogenic (Jun 16, 1988)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 14347873, 3055413
SCV000756580	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 29, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1469094, 16620552, 28492532
SCV005367700	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Likely Pathogenic (Aug 16, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000039917

OMIM

no assertion criteria provided

Pathogenic
(Jun 16, 1988)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000756580

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 29, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005367700

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Likely Pathogenic
(Aug 16, 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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA.

EGEBERG O.

Thromb Diath Haemorrh. 1965 Jun 15;13:516-30. No abstract available.

PubMed [citation]

PMID:: 14347873

Antithrombin Oslo: type Ib classification of the first reported antithrombin-deficient family, with a review of hereditary antithrombin variants.

Hultin MB, McKay J, Abildgaard U.

Thromb Haemost. 1988 Jun 16;59(3):468-73. Review.

PubMed [citation]

PMID:: 3055413

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000039917.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

This variant, designated AT-III Oslo, was found in the family first described as an example of thrombophilia due to deficiency of AT-III (613118) by Egeberg (1965). Hultin et al. (1988) provided further information. AT-III Oslo is a type I form of deficiency. AT-III protein is decreased in both the immunologic and the functional assay.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000756580.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies using both patient cells and transfected cell lines have shown that cells carrying this missense variant demonstrate reduced antithrombin activity and antigen levels (PMID: 1469094, 16620552). This variant has been reported to segregate with antithrombin deficiency in several families (PMID: 1469094, 16620552). ClinVar contains an entry for this variant (Variation ID: 18003). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 436 of the SERPINC1 protein (p.Ala436Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.

#	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

From Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005367700.1

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

Description

The c.1306G>A (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 436 (p.Ala436Thr). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL with either a family history of antithrombin activity levels of < 0.8 IU/mL or an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. One more proband is reported with antithrombin activity levels of < 0.8 IU/mL but no repeat testing or family history is specified so 0.5 point is awarded (PS4_Moderate; PMID:3055413, 1469094). The variant has been reported to segregate with autosomal dominant antithrombin deficiency in 11 affected meioses from one family (PP1_Moderate; PMIDs:1469094, 3055413). The computational predictor REVEL gives a score of 0.778, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1_Moderate, PM2_Supporting, PS4_Moderate, PP3.

#	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: Oct 20, 2024

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