NM_000488.4(SERPINC1):c.1246G>T (p.Ala416Ser) AND Hereditary antithrombin deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jan 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000019639.50

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1246G>T (p.Ala416Ser)]

NM_000488.4(SERPINC1):c.1246G>T (p.Ala416Ser)

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.1246G>T (p.Ala416Ser)

Other names:

A384S; AT-III Cambridge II

HGVS:

NC_000001.11:g.173904038C>A
NG_012462.1:g.18341G>T
NM_000488.4:c.1246G>TMANE SELECT
NM_001365052.2:c.1102G>T
NM_001386302.1:c.1369G>T
NM_001386303.1:c.1327G>T
NM_001386304.1:c.1225G>T
NM_001386305.1:c.1189G>T
NM_001386306.1:c.1030G>T
NP_000479.1:p.Ala416Ser
NP_000479.1:p.Ala416Ser
NP_001351981.1:p.Ala368Ser
NP_001373231.1:p.Ala457Ser
NP_001373232.1:p.Ala443Ser
NP_001373233.1:p.Ala409Ser
NP_001373234.1:p.Ala397Ser
NP_001373235.1:p.Ala344Ser
LRG_577t1:c.1246G>T
LRG_577:g.18341G>T
LRG_577p1:p.Ala416Ser
NC_000001.10:g.173873176C>A
NM_000488.3:c.1246G>T
P01008:p.Ala416Ser

Protein change:

A344S; ALA384SER

Links:

UniProtKB: P01008#VAR_007071; OMIM: 107300.0027; dbSNP: rs121909548

NCBI 1000 Genomes Browser:

rs121909548

Molecular consequence:

NM_000488.4:c.1246G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1102G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1369G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1327G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1225G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1189G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1030G>T - 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

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PIGG [Rhinolophus ferrumequinum]
PIGG [Rhinolophus ferrumequinum]
Gene ID:117022172

Gene
Spectrin
Spectrin
A high molecular weight (220-250 kDa) water-soluble protein which can be extracted from erythrocyte ghosts in low ionic strength buffers. The protein contains no lipids or car...<br/>Year introduced: 1984(1977)

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039937	OMIM	no assertion criteria provided	Pathogenic (Jul 22, 1991)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 2012760, 1906811
SCV000190628	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000254588	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002512242	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002515500	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	no assertion criteria provided	Likely pathogenic	unknown	clinical testing

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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	clinical testing, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The incidence of dysfunctional antithrombin variants: four cases in 210 patients with thromboembolic disease.

Harper PL, Luddington RJ, Daly M, Bruce D, Williamson D, Edgar PF, Perry DJ, Carrell RW.

Br J Haematol. 1991 Mar;77(3):360-4.

PubMed [citation]

PMID:: 2012760

Antithrombin Cambridge II, 384 Ala to Ser. Further evidence of the role of the reactive centre loop in the inhibitory function of the serpins.

Perry DJ, Daly M, Harper PL, Tait RC, Price J, Walker ID, Carrell RW.

FEBS Lett. 1991 Jul 22;285(2):248-50.

PubMed [citation]

PMID:: 1906811

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000039937.1

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

Description

Harper et al. (1991) identified AT-III Cambridge II, which has a substitution of serine for alanine-384. This mutation occurs at the same codon as AT-III Cambridge I (107300.0007). Perry et al. (1991) identified 4 unrelated persons with an identical antithrombin variant, associated in one of them with episodes of recurrent venous thromboses (613118). In each case, the plasma antithrombin concentration was normal and the only functional abnormality was a minor but consistent decrease in the heparin-induced thrombin inhibition, suggesting a mutation at or near the reactive center of the molecule. Amplification and direct sequencing of exon 6 showed a G-to-T mutation at nucleotide 1246, which corresponded to a substitution of serine for alanine at residue 384.

#	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 CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190628.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000254588.8

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

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512242.1

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

Description

ACMG classification criteria: PS3 supporting, PS4 strong, PM3 moderate

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

From ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002515500.1

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

Last Updated: Nov 3, 2024

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