NM_000488.4(SERPINC1):c.1315C>A (p.Pro439Thr) AND Hereditary antithrombin deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 21, 2023
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:: RCV003330321.4

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1315C>A (p.Pro439Thr)]

NM_000488.4(SERPINC1):c.1315C>A (p.Pro439Thr)

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.1315C>A (p.Pro439Thr)

Other names:

NM_000488.3(SERPINC1):c.1315C>A; p.Pro439Thr

HGVS:

NC_000001.11:g.173903969G>T
NG_012462.1:g.18410C>A
NM_000488.4:c.1315C>AMANE SELECT
NM_001365052.2:c.1171C>A
NM_001386302.1:c.1438C>A
NM_001386303.1:c.1396C>A
NM_001386304.1:c.1294C>A
NM_001386305.1:c.1258C>A
NM_001386306.1:c.1099C>A
NP_000479.1:p.Pro439Thr
NP_000479.1:p.Pro439Thr
NP_001351981.1:p.Pro391Thr
NP_001373231.1:p.Pro480Thr
NP_001373232.1:p.Pro466Thr
NP_001373233.1:p.Pro432Thr
NP_001373234.1:p.Pro420Thr
NP_001373235.1:p.Pro367Thr
LRG_577t1:c.1315C>A
LRG_577:g.18410C>A
LRG_577p1:p.Pro439Thr
NC_000001.10:g.173873107G>T
NC_000001.10:g.173873107G>T
NM_000488.3:c.1315C>A

Protein change:

P367T

Links:

dbSNP: rs1487411568

NCBI 1000 Genomes Browser:

rs1487411568

Molecular consequence:

NM_000488.4:c.1315C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1171C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1438C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1396C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1294C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1258C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1099C>A - 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
SCV004037396	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Pathogenic (Sep 21, 2023)	germline	curation	Citation Link,
SCV004293828	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 1, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16705712, 23910795, 28300866, 18480576, 1469094, 24814625, 28229161, 29153735, 31030036, 31064749, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004037396

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Pathogenic
(Sep 21, 2023)

germline

curation

Citation Link,

SCV004293828

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 1, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

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

Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene.

Picard V, Nowak-Göttl U, Biron-Andreani C, Fouassier M, Frere C, Goualt-Heilman M, de Maistre E, Regina S, Rugeri L, Ternisien C, Trichet C, Vergnes C, Aiach M, Alhenc-Gelas M.

Hum Mutat. 2006 Jun;27(6):600. Erratum in: Hum Mutat. 2006 Nov;27(11):1160.

PubMed [citation]

PMID:: 16705712

Type II antithrombin deficiency caused by a founder mutation Pro73Leu in the Finnish population: clinical picture.

Puurunen M, Salo P, Engelbarth S, Javela K, Perola M.

J Thromb Haemost. 2013 Oct;11(10):1844-9. doi: 10.1111/jth.12364.

PubMed [citation]

PMID:: 23910795

See all PubMed Citations (11)

Details of each submission

From Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV004037396.1

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

Description

The c.1315C>A (p.Pro439Thr) variant is reported at an MAF of (FAF not available), 1/68048 alleles in the non-Finnish European population in gnomAD v3.1.1 and meets criteria for PM2_Supporting (threshold <0.00002). It has a REVEL score of 0.88 and meets criteria for PP3. Several probands can be counted across the literature, who meet phenotype criteria for AT deficiency with a mix of repeat sampling, meeting PP4 and PS4. Four segregations are counted across two families meeting criteria for PP1_Moderate. Expression of mutant AT, 439Thr-AT, in HEK293 cells described in PMID: 18480576 revealed decrease in AT secretion, meeting criteria for PS3_Supporting. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4, PP1_Moderate, PP3, PP4, PM2_Supporting, PS3_Supporting.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004293828.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 439 of the SERPINC1 protein (p.Pro439Thr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro439 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16705712, 23910795, 28300866; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 18480576). 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 expected to disrupt SERPINC1 protein function. ClinVar contains an entry for this variant (Variation ID: 627228). This variant is also known as P407T. This missense change has been observed in individual(s) with antithrombin III deficiency (PMID: 1469094, 24814625, 28229161, 29153735, 31030036, 31064749).

#	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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