NM_000488.4(SERPINC1):c.1311C>G (p.Asn437Lys) AND Hereditary antithrombin deficiency

Germline classification:: Pathogenic (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:: RCV003527184.3

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1311C>G (p.Asn437Lys)]

NM_000488.4(SERPINC1):c.1311C>G (p.Asn437Lys)

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.1311C>G (p.Asn437Lys)

Other names:

NM_001386306.1:c.1095C>G

HGVS:

NC_000001.11:g.173903973G>C
NG_012462.1:g.18406C>G
NM_000488.4:c.1311C>GMANE SELECT
NM_001365052.2:c.1167C>G
NM_001386302.1:c.1434C>G
NM_001386303.1:c.1392C>G
NM_001386304.1:c.1290C>G
NM_001386305.1:c.1254C>G
NM_001386306.1:c.1095C>G
NP_000479.1:p.Asn437Lys
NP_000479.1:p.Asn437Lys
NP_001351981.1:p.Asn389Lys
NP_001373231.1:p.Asn478Lys
NP_001373232.1:p.Asn464Lys
NP_001373233.1:p.Asn430Lys
NP_001373234.1:p.Asn418Lys
NP_001373235.1:p.Asn365Lys
LRG_577t1:c.1311C>G
LRG_577:g.18406C>G
LRG_577p1:p.Asn437Lys
NC_000001.10:g.173873111G>C
NM_000488.3:c.1311C>G

Protein change:

N365K

Molecular consequence:

NM_000488.4:c.1311C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1167C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1434C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1392C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1290C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1254C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1095C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004293829	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1469094, 1796410, 12755798, 33725558, 28492532
SCV005061619	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Pathogenic (Feb 19, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004293829

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 13, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005061619

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Pathogenic
(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	clinical testing, curation

Citations

PubMed

Pleiotropic effects of antithrombin strand 1C substitution mutations.

Lane DA, Olds RJ, Conard J, Boisclair M, Bock SC, Hultin M, Abildgaard U, Ireland H, Thompson E, Sas G, et al.

J Clin Invest. 1992 Dec;90(6):2422-33.

PubMed [citation]

PMID:: 1469094
PMCID:: PMC443398

Antithrombin III: a database of mutations.

Lane DA, Ireland H, Olds RJ, Thein SL, Perry DJ, Aiach M.

Thromb Haemost. 1991 Dec 2;66(6):657-61.

PubMed [citation]

PMID:: 1796410

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004293829.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 437 of the SERPINC1 protein (p.Asn437Lys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with antithrombin III deficiency (PMID: 1469094, 1796410, 12755798, 33725558). It has also been observed to segregate with disease in related individuals. This variant is also known as Asn405Lys. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. 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 Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005061619.1

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

Description

The c.1311C>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of asparagine by lysine at amino acid 437 (p.Asn437Lys). The computational predictor REVEL gives a score of 0.683, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. The variant has been reported in at least 8 probands with AT deficiency in the literature (7.5 points applied PMID 28300866; PMID 24684277; PMID 12755798; PMID 1469094). The variant has been reported to segregate with autosomal dominant hereditary antithrombin deficiency in 7 affected family meioses from 4 families (PP1_strong; PMID: 1469094; PMID: 12755798; PMID: 28300866). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PP1_Strong, PS4, PP3.

#	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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