NM_000488.4(SERPINC1):c.1274G>C (p.Arg425Pro) AND Hereditary antithrombin deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 3, 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:: RCV000019625.28

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1274G>C (p.Arg425Pro)]

NM_000488.4(SERPINC1):c.1274G>C (p.Arg425Pro)

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.1274G>C (p.Arg425Pro)

Other names:

R393P; NM_000488.4(SERPINC1):c.1274G>C

HGVS:

NC_000001.11:g.173904010C>G
NG_012462.1:g.18369G>C
NM_000488.4:c.1274G>CMANE SELECT
NM_001365052.2:c.1130G>C
NM_001386302.1:c.1397G>C
NM_001386303.1:c.1355G>C
NM_001386304.1:c.1253G>C
NM_001386305.1:c.1217G>C
NM_001386306.1:c.1058G>C
NP_000479.1:p.Arg425Pro
NP_001351981.1:p.Arg377Pro
NP_001373231.1:p.Arg466Pro
NP_001373232.1:p.Arg452Pro
NP_001373233.1:p.Arg418Pro
NP_001373234.1:p.Arg406Pro
NP_001373235.1:p.Arg353Pro
LRG_577:g.18369G>C
NC_000001.10:g.173873148C>G
P01008:p.Arg425Pro

Protein change:

R353P; ARG393PRO

Links:

UniProtKB: P01008#VAR_007076; OMIM: 107300.0010; dbSNP: rs121909549

NCBI 1000 Genomes Browser:

rs121909549

Molecular consequence:

NM_000488.4:c.1274G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1130G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1397G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1355G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1253G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1217G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1058G>C - 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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039923	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1989)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 3828226, 2917133
SCV005367705	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Likely Pathogenic (Jul 3, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000039923

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1989)

germline

literature only

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

SCV005367705

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Likely Pathogenic
(Jul 3, 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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Antithrombin III Pescara: a defective AT III variant with no alterations of plasma crossed immunoelectrophoresis, but with an abnormal crossed immunoelectrofocusing pattern.

Leone G, De Stefano V, Di Donfrancesco A, Ferrelli R, Traisci G, Bizzi B.

Br J Haematol. 1987 Feb;65(2):187-91.

PubMed [citation]

PMID:: 3828226

Antithrombin Sheffield: amino acid substitution at the reactive site (Arg393 to His) causing thrombosis.

Lane DA, Erdjument H, Flynn A, Di Marzo V, Panico M, Morris HR, Greaves M, Dolan G, Preston FE.

Br J Haematol. 1989 Jan;71(1):91-6.

PubMed [citation]

PMID:: 2917133

Details of each submission

From OMIM, SCV000039923.1

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

Description

AT-III Pescara, described by Leone et al. (1987) in a family with a high incidence of thrombosis (613118), was shown by Lane et al. (1989) to have a CGT-to-CCT change in the AT3 gene, resulting in substitution of proline for arginine-393. The defect concerned binding to serine proteases.

#	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, SCV005367705.1

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

Description

The c.1274G>C variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by proline at amino acid 425 (p.Arg425Pro). This variant has been reported in one proband meeting an antithrombin activity level of < 0.8 IU/mL with a family history of antithrombin activity levels of < 0.8 IU/mL (PS4_Supporting; PMID:3828226, 2722864). The variant has been reported to segregate with hereditary antithrombin deficiency in seven affected meioses from the proband's family (PP1_Moderate; PMID: 3828226). The computational predictor REVEL gives a score of 0.878, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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: PM2_Supporting, PS4_Supporting, PP3, PM5, PP1_Moderate.

#	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

ClinVar

Relating variation to medicine