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NM_000488.4(SERPINC1):c.1277C>G (p.Ser426Trp) AND Hereditary antithrombin deficiency

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 5, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001908898.4

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1277C>G (p.Ser426Trp)]

NM_000488.4(SERPINC1):c.1277C>G (p.Ser426Trp)

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.1277C>G (p.Ser426Trp)
HGVS:
  • NC_000001.11:g.173904007G>C
  • NG_012462.1:g.18372C>G
  • NM_000488.4:c.1277C>GMANE SELECT
  • NM_001365052.2:c.1133C>G
  • NM_001386302.1:c.1400C>G
  • NM_001386303.1:c.1358C>G
  • NM_001386304.1:c.1256C>G
  • NM_001386305.1:c.1220C>G
  • NM_001386306.1:c.1061C>G
  • NP_000479.1:p.Ser426Trp
  • NP_001351981.1:p.Ser378Trp
  • NP_001373231.1:p.Ser467Trp
  • NP_001373232.1:p.Ser453Trp
  • NP_001373233.1:p.Ser419Trp
  • NP_001373234.1:p.Ser407Trp
  • NP_001373235.1:p.Ser354Trp
  • LRG_577:g.18372C>G
  • NC_000001.10:g.173873145G>C
Protein change:
S354W
Links:
dbSNP: rs121909550
NCBI 1000 Genomes Browser:
rs121909550
Molecular consequence:
  • NM_000488.4:c.1277C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365052.2:c.1133C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386302.1:c.1400C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386303.1:c.1358C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386304.1:c.1256C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386305.1:c.1220C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001386306.1:c.1061C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002169115Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Sep 5, 2021) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Antithrombin III Milano 2: a single base substitution in the thrombin binding domain detected with PCR and direct genomic sequencing.

Olds RJ, Lane D, Caso R, Tripodi A, Mannucci PM, Thein SL.

Nucleic Acids Res. 1989 Dec 25;17(24):10511. No abstract available.

PubMed [citation]
PMID:
2602168
PMCID:
PMC335336

Abnormal antithrombin III with defective serine protease binding (antithrombin III "Denver").

Sambrano JE, Jacobson LJ, Reeve EB, Manco-Johnson MJ, Hathaway WE.

J Clin Invest. 1986 Mar;77(3):887-93.

PubMed [citation]
PMID:
3512602
PMCID:
PMC423475
See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002169115.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser426 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2602168, 3512602, 3563966, 18954896, 20088933, 25298121). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with features of antithrombin III deficiency (PMID: 28174134, 29296762). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tryptophan at codon 426 of the SERPINC1 protein (p.Ser426Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024