NM_000488.4(SERPINC1):c.1011A>G (p.Gln337=) AND Hereditary antithrombin deficiency

Germline classification:: Benign (4 submissions)
Last evaluated:: Jul 25, 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:: RCV000292511.15

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1011A>G (p.Gln337=)]

NM_000488.4(SERPINC1):c.1011A>G (p.Gln337=)

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.1011A>G (p.Gln337=)

Other names:

NM_000488.3(SERPINC1):c.1011A>G; p.Gln337=

HGVS:

NC_000001.11:g.173909694T>C
NG_012462.1:g.12685A>G
NM_000488.4:c.1011A>GMANE SELECT
NM_001365052.2:c.867A>G
NM_001386302.1:c.1134A>G
NM_001386303.1:c.1092A>G
NM_001386304.1:c.990A>G
NM_001386305.1:c.954A>G
NM_001386306.1:c.795A>G
NP_000479.1:p.Gln337=
NP_000479.1:p.Gln337=
NP_001351981.1:p.Gln289=
NP_001373231.1:p.Gln378=
NP_001373232.1:p.Gln364=
NP_001373233.1:p.Gln330=
NP_001373234.1:p.Gln318=
NP_001373235.1:p.Gln265=
LRG_577t1:c.1011A>G
LRG_577:g.12685A>G
LRG_577p1:p.Gln337=
NC_000001.10:g.173878832T>C
NM_000488.3:c.1011A>G

Links:

dbSNP: rs5878

NCBI 1000 Genomes Browser:

rs5878

Molecular consequence:

NM_000488.4:c.1011A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001365052.2:c.867A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386302.1:c.1134A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386303.1:c.1092A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386304.1:c.990A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386305.1:c.954A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386306.1:c.795A>G - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000351481	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000999945	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002054786	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004037399	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Benign (Jul 25, 2023)	germline	curation	Citation Link

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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, curation
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000351481.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#	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, SCV000999945.5

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002054786.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV004037399.1

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

Description

The variant is reported at a popmax FAF of 0.7651 and the highest MAF of 0.7792 (78%; 19440/24948 alleles with 7592 homozygotes) in the African/African-American population in gnomAD v2.1.1, meeting criteria for BA1 (MAF >0.002). The variant is reported in 1 individual with normal antithrombin levels. SpliceAI and VarSeak predict no impact on splicing and PhyloP gives a conservation score of 0.028 (<0.1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BS2_Supporting, BP4, BP7.

#	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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