NM_000488.4(SERPINC1):c.235C>A (p.Arg79Ser) AND Hereditary antithrombin deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 9, 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:: RCV000019631.29

Allele description [Variation Report for NM_000488.4(SERPINC1):c.235C>A (p.Arg79Ser)]

NM_000488.4(SERPINC1):c.235C>A (p.Arg79Ser)

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.235C>A (p.Arg79Ser)

Other names:

R47S; NM_000488.4(SERPINC1):c.235C>A

HGVS:

NC_000001.11:g.173914726G>T
NG_012462.1:g.7653C>A
NM_000488.4:c.235C>AMANE SELECT
NM_001365052.2:c.91C>A
NM_001386302.1:c.235C>A
NM_001386303.1:c.316C>A
NM_001386304.1:c.235C>A
NM_001386305.1:c.235C>A
NM_001386306.1:c.235C>A
NP_000479.1:p.Arg79Ser
NP_001351981.1:p.Arg31Ser
NP_001373231.1:p.Arg79Ser
NP_001373232.1:p.Arg106Ser
NP_001373233.1:p.Arg79Ser
NP_001373234.1:p.Arg79Ser
NP_001373235.1:p.Arg79Ser
LRG_577:g.7653C>A
NC_000001.10:g.173883864G>T
P01008:p.Arg79Ser

Protein change:

R106S; ARG47SER

Links:

UniProtKB: P01008#VAR_007039; OMIM: 107300.0016; dbSNP: rs121909547

NCBI 1000 Genomes Browser:

rs121909547

Molecular consequence:

NM_000488.4:c.235C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.91C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.235C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.316C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.235C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.235C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.235C>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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Mus musculus jumonji C domain-containing histone demethylase 1 homolog D (S. cer...
Mus musculus jumonji C domain-containing histone demethylase 1 homolog D (S. cerevisiae), mRNA (cDNA clone IMAGE:3488682), partial cds
gi|13938092|gb|BC007161.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039929	OMIM	no assertion criteria provided	Pathogenic (Jun 18, 1990)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV005061624	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Likely Pathogenic (May 9, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000039929

OMIM

no assertion criteria provided

Pathogenic
(Jun 18, 1990)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV005061624

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Likely Pathogenic
(May 9, 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	curation

Citations

PubMed

Antithrombin Rouen-IV 24 Arg----Cys. The amino-terminal contribution to heparin binding.

Borg JY, Brennan SO, Carrell RW, George P, Perry DJ, Shaw J.

FEBS Lett. 1990 Jun 18;266(1-2):163-6.

PubMed [citation]

PMID:: 2365065

Details of each submission

From OMIM, SCV000039929.2

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

Description

Borg et al. (1988) identified heterozygosity for an arg47-to-ser (R47S) substitution in the AT3 gene in a 40-year-old man who was admitted to hospital with a sudden myocardial infarction that lacked extensive coronary artery disease. His 13-year-old daughter displayed the same antithrombin abnormality. The variant, designated AT-III Rouen II, showed defective heparin and heparan sulfate activities. There was no definite family history of thrombosis.

#	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 Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005061624.1

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

Description

The c.235C>A variant in SEPRINC1 is a missense variant predicted to cause substitution of arginine by serine at amino acid 79 (p.Arg79Ser). This variant has been reported in one family with an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. (PS4_Supporting; PMID:3350974). This variant is absent from gnomAD v[2.1.1] (PM2_Supporting). This variant resides within a region, Arg79, of SERPINC1 that is defined as a critical functional domain that would impact heparin binding site residues by the ClinGen Thrombosis Variant Curation Expert Panel (PM1). Another missense variant c.236G>A (p.Arg79His) (ClinVarID:18014) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis Variant Curation Expert Panel (PM5). The computational predictor REVEL gives a score of 0.718, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). 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 Variant Curation Expert Panel: PM1, PM5, PP3, PM2_Supporting, PS4_Supporting. (Required: ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval)

#	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 8, 2024

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