NM_000488.4(SERPINC1):c.1301T>G (p.Phe434Cys) AND Hereditary antithrombin deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 19, 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:: RCV000852011.2

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1301T>G (p.Phe434Cys)]

NM_000488.4(SERPINC1):c.1301T>G (p.Phe434Cys)

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.1301T>G (p.Phe434Cys)

Other names:

NM_000488.4(SERPINC1):c.1301T>G; p.Phe434Cys

HGVS:

NC_000001.11:g.173903983A>C
NG_012462.1:g.18396T>G
NM_000488.4:c.1301T>GMANE SELECT
NM_001365052.2:c.1157T>G
NM_001386302.1:c.1424T>G
NM_001386303.1:c.1382T>G
NM_001386304.1:c.1280T>G
NM_001386305.1:c.1244T>G
NM_001386306.1:c.1085T>G
NP_000479.1:p.Phe434Cys
NP_000479.1:p.Phe434Cys
NP_001351981.1:p.Phe386Cys
NP_001373231.1:p.Phe475Cys
NP_001373232.1:p.Phe461Cys
NP_001373233.1:p.Phe427Cys
NP_001373234.1:p.Phe415Cys
NP_001373235.1:p.Phe362Cys
LRG_577t1:c.1301T>G
LRG_577:g.18396T>G
LRG_577p1:p.Phe434Cys
NC_000001.10:g.173873121A>C
NM_000488.3:c.1301T>G

Protein change:

F362C

Links:

dbSNP: rs1572084546

NCBI 1000 Genomes Browser:

rs1572084546

Molecular consequence:

NM_000488.4:c.1301T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1157T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1424T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1382T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1280T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1244T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1085T>G - 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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SDC1 [Nomascus leucogenys]
SDC1 [Nomascus leucogenys]
Gene ID:100604383

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000899469	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
SCV005061634	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Uncertain Significance (Feb 19, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000899469

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]

SCV005061634

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Uncertain Significance
(Feb 19, 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
European	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, et al.

Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.

PubMed [citation]

PMID:: 31064749
PMCID:: PMC6993014

Details of each submission

From NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899469.1

#	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 Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005061634.1

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

Description

The c.1301T>G (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of phenylalanine by cystenine at amino acid 434 (p.Phe434Cys). This variant has been reported in 1 proband meeting an antithrombin activity level of < 0.8 IU/mL with repeat testing overtime (PS4_Supporting; PMID:1469094). This variant is absent from gnomAD v3.1.2 and v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.921, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1302C>A (p.Phe434Leu) (ClinVarID:2202884) in the same codon has been classified as likely pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2, PM5, PS4_Supporting. (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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