NM_000488.4(SERPINC1):c.235C>T (p.Arg79Cys) AND Hereditary antithrombin deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000019620.32

Allele description [Variation Report for NM_000488.4(SERPINC1):c.235C>T (p.Arg79Cys)]

NM_000488.4(SERPINC1):c.235C>T (p.Arg79Cys)

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>T (p.Arg79Cys)

Other names:

R47C

HGVS:

NC_000001.11:g.173914726G>A
NG_012462.1:g.7653C>T
NM_000488.4:c.235C>TMANE SELECT
NM_001365052.2:c.91C>T
NM_001386302.1:c.235C>T
NM_001386303.1:c.316C>T
NM_001386304.1:c.235C>T
NM_001386305.1:c.235C>T
NM_001386306.1:c.235C>T
NP_000479.1:p.Arg79Cys
NP_000479.1:p.Arg79Cys
NP_001351981.1:p.Arg31Cys
NP_001373231.1:p.Arg79Cys
NP_001373232.1:p.Arg106Cys
NP_001373233.1:p.Arg79Cys
NP_001373234.1:p.Arg79Cys
NP_001373235.1:p.Arg79Cys
LRG_577t1:c.235C>T
LRG_577:g.7653C>T
LRG_577p1:p.Arg79Cys
NC_000001.10:g.173883864G>A
NM_000488.3:c.235C>T
P01008:p.Arg79Cys

Protein change:

R106C; ARG47CYS

Links:

UniProtKB: P01008#VAR_007037; OMIM: 107300.0003; dbSNP: rs121909547

NCBI 1000 Genomes Browser:

rs121909547

Molecular consequence:

NM_000488.4:c.235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.91C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.235C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary antithrombin deficiency
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
SCV000039918	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1996)	germline	literature only	PubMed (12) [See all records that cite these PMIDs] 6582486, 7082587, 6871478, 3413737, 6204398, 3960724, 3775688, 6636045, 3563974, 3715788, 3605071, 2615648
SCV000899613	NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31064749
SCV001391190	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 24, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 3960724, 6582486, 21325262, 24162787, 28300866, 22498748, 27322195, 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735, 28492532
SCV002059060	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:2615648,
SCV002499590	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
European	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

A new familial variant of antithrombin III: 'antithrombin III Paris'.

Wolf M, Boyer C, Lavergne JM, Larrieu MJ.

Br J Haematol. 1982 Jun;51(2):285-95.

PubMed [citation]

PMID:: 7082587

Antithrombin III (AT III) Padua2: a "new" congenital abnormality with defective heparin co-factor activities but no thrombotic disease.

Girolami A, Fabris F, Cappellato G, Sainati L, Boeri G.

Blut. 1983 Aug;47(2):93-103.

PubMed [citation]

PMID:: 6871478

See all PubMed Citations (27)

Details of each submission

From OMIM, SCV000039918.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (12)

Description

AT-III Toyama was described by Sakuragawa et al. (1983). In a patient with recurrent thrombophlebitis and deficiency of AT-III (613118), Koide et al. (1984) identified homozygosity for AT-III Toyama, an arg47-to-cys substitution. Members of the family who were heterozygous for the mutation were asymptomatic.

This mutation has also been described as AT-III Paris (Wolf et al., 1982), AT-III Padua-2 (Girolami et al., 1983), AT-III Tours (Duchange et al., 1986), AT-III Barcelona-2 (Fontcuberta et al., 1988), AT-III Alger (Fischer et al., 1986), AT-III Amiens, and AT-III Paris-2.

Chasse et al. (1984) identified the abnormality in heterozygous state in 9 members of a French family, all without thrombotic complications. Duchange et al. (1986) confirmed that the mutation (AT-III Tours) in this family was a C-to-T transition leading to an arg47-to-cys substitution. The deficiency in AT-III Tours shows retention of normal activity in the absence of heparin and diminished activity in the presence of heparin, with a decrease or complete loss of heparin-binding ability. Most type 3 deficiencies are silent in the heterozygous state and associated with severe thrombotic disorders only in homozygotes (Boyer et al., 1986; Sakuragawa et al., 1983; Duchange et al., 1987).

This variant, described in homozygous form by Fischer et al. (1986), was shown by Brunel et al. (1987) also to have substitution of cysteine for arginine-47. The same mutation was identified by Perry and Carrell (1989).

#	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 NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899613.1

#	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 Invitae, SCV001391190.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the SERPINC1 protein (p.Arg79Cys). This variant is present in population databases (rs121909547, gnomAD 0.02%). This missense change has been observed in individuals with antithrombin III deficiency (PMID: 3960724, 6582486, 21325262, 24162787, 25837307, 28300866). It has also been observed to segregate with disease in related individuals. This variant is also known as R47C, Arg47Cys, Antithrombin III Toyama, Antithrombin III Alger, and Antithrombin III tours. ClinVar contains an entry for this variant (Variation ID: 18004). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINC1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 22498748, 27322195). This variant disrupts the p.Arg79 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 3billion, SCV002059060.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018004, PMID:6582486, PS1_S). A different missense change at the same codon has been reported to be associated with SERPINC1 related disorder (ClinVar ID: VCV000018015, PMID:2615648,3350974, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.743, PP3_P). A missense variant is a common mechanism associated with Thrombophilia due to antithrombin III deficiency (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

From ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002499590.2

#	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

Last Updated: Feb 28, 2024

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