NM_000488.4(SERPINC1):c.89T>A (p.Val30Glu) AND Hereditary antithrombin deficiency

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Jan 17, 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:: RCV000019628.56

Allele description [Variation Report for NM_000488.4(SERPINC1):c.89T>A (p.Val30Glu)]

NM_000488.4(SERPINC1):c.89T>A (p.Val30Glu)

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.89T>A (p.Val30Glu)

HGVS:

NC_000001.11:g.173914872A>T
NG_012462.1:g.7507T>A
NM_000488.4:c.89T>AMANE SELECT
NM_001365052.2:c.-56T>A
NM_001386302.1:c.89T>A
NM_001386303.1:c.170T>A
NM_001386304.1:c.89T>A
NM_001386305.1:c.89T>A
NM_001386306.1:c.89T>A
NP_000479.1:p.Val30Glu
NP_000479.1:p.Val30Glu
NP_001373231.1:p.Val30Glu
NP_001373232.1:p.Val57Glu
NP_001373233.1:p.Val30Glu
NP_001373234.1:p.Val30Glu
NP_001373235.1:p.Val30Glu
LRG_577t1:c.89T>A
LRG_577:g.7507T>A
LRG_577p1:p.Val30Glu
NC_000001.10:g.173884010A>T
NM_000488.3:c.89T>A
P01008:p.Val30Glu

Protein change:

V57E

Links:

UniProtKB: P01008#VAR_007032; OMIM: 107300.0013; dbSNP: rs2227624

NCBI 1000 Genomes Browser:

rs2227624

Molecular consequence:

NM_001365052.2:c.-56T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000488.4:c.89T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.89T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.170T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.89T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.89T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.89T>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039926	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 1992)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 3472589, 1977621, 1483705
SCV000253285	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 17, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000899978	NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31064749
SCV001258216	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV002499587	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004099398	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Oct 30, 2023)	germline	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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
European	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Identification and characterization of a new antithrombin III familial variant (AT Dublin) with possible increased frequency in children with cancer.

Daly M, O'Meara A, Hallinan FM.

Br J Haematol. 1987 Apr;65(4):457-62.

PubMed [citation]

PMID:: 3472589

Antithrombin Dublin (-3 Val----Glu): an N-terminal variant which has an aberrant signal peptidase cleavage site.

Daly M, Bruce D, Perry DJ, Price J, Harper PL, O'Meara A, Carrell RW.

FEBS Lett. 1990 Oct 29;273(1-2):87-90.

PubMed [citation]

PMID:: 1977621

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000039926.1

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

Description

AT-III Dublin was described by Daly et al. (1987) in heterozygous state in 3 Irish individuals with no evidence of hypercoagulation-related problems. In the course of sequencing the AT3 gene in an AT-III Dublin heterozygote, Daly et al. (1990) identified a valine-to-glutamic acid substitution at position -3 in the signal peptide. A second, unrelated individual being investigated for recurrent thromboses was found to be heterozygous for same mutation. N-terminal sequencing of the antithrombin protein from both heterozygotes showed a truncated antithrombin in which the N-terminal dipeptide is absent. Daly et al. (1990) proposed that the prepeptide mutation redirects signal peptidase cleavage to a site 2 amino acids downstream into the mature protein.

Durr et al. (1992) found this mutation in southwest Germans and Portuguese, with frequencies of 0.007 and 0.00024, respectively.

#	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, SCV000253285.8

#	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 NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899978.1

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

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

From Illumina Laboratory Services, Illumina, SCV001258216.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

#	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 ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002499587.3

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

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004099398.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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