NM_000488.4(SERPINC1):c.886G>C (p.Ala296Pro) AND Hereditary antithrombin deficiency

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Oct 23, 2022
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:: RCV001099621.19

Allele description [Variation Report for NM_000488.4(SERPINC1):c.886G>C (p.Ala296Pro)]

NM_000488.4(SERPINC1):c.886G>C (p.Ala296Pro)

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.886G>C (p.Ala296Pro)

HGVS:

NC_000001.11:g.173909819C>G
NG_012462.1:g.12560G>C
NM_000488.4:c.886G>CMANE SELECT
NM_001365052.2:c.742G>C
NM_001386302.1:c.1009G>C
NM_001386303.1:c.967G>C
NM_001386304.1:c.865G>C
NM_001386305.1:c.829G>C
NM_001386306.1:c.670G>C
NP_000479.1:p.Ala296Pro
NP_000479.1:p.Ala296Pro
NP_001351981.1:p.Ala248Pro
NP_001373231.1:p.Ala337Pro
NP_001373232.1:p.Ala323Pro
NP_001373233.1:p.Ala289Pro
NP_001373234.1:p.Ala277Pro
NP_001373235.1:p.Ala224Pro
LRG_577t1:c.886G>C
LRG_577:g.12560G>C
LRG_577p1:p.Ala296Pro
NC_000001.10:g.173878957C>G
NM_000488.3:c.886G>C

Protein change:

A224P

Links:

dbSNP: rs372820797

NCBI 1000 Genomes Browser:

rs372820797

Molecular consequence:

NM_000488.4:c.886G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.742G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1009G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.967G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.865G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.829G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.670G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

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cytochrome oxidase subunit 1, partial (mitochondrion) [Rasbora paucisqualis]
cytochrome oxidase subunit 1, partial (mitochondrion) [Rasbora paucisqualis]
gi|1817212623|gb|QIF10977.1|

Protein
JGI_CAAP8993.rev NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7715251 3'...
JGI_CAAP8993.rev NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7715251 3', mRNA sequence
gi|58788729|gnl|dbEST|27682121|gb|C 07.1|

Nucleotide
AGENCOURT_77726110 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8642054 5', ...
AGENCOURT_77726110 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8642054 5', mRNA sequence
gi|95011529|gnl|dbEST|39153530|gb|E 13.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190629	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV001256093	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002788339	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 16, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003270931	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 23, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22627591, 28492532
SCV004014040	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing

Citations

PubMed

Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort.

Caspers M, Pavlova A, Driesen J, Harbrecht U, Klamroth R, Kadar J, Fischer R, Kemkes-Matthes B, Oldenburg J.

Thromb Haemost. 2012 Aug;108(2):247-57. doi: 10.1160/TH11-12-0875. Epub 2012 May 25.

PubMed [citation]

PMID:: 22627591

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190629.1

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

#	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 Illumina Laboratory Services, Illumina, SCV001256093.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002788339.1

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003270931.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

ClinVar contains an entry for this variant (Variation ID: 161390). 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. 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. This missense change has been observed in individual(s) with AT deficiency (PMID: 22627591). This variant is present in population databases (rs372820797, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 296 of the SERPINC1 protein (p.Ala296Pro).

#	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 ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV004014040.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)
2	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	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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