NM_000488.4(SERPINC1):c.870C>T (p.Phe290=) AND Hereditary antithrombin deficiency

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Aug 16, 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:: RCV000306901.16

Allele description [Variation Report for NM_000488.4(SERPINC1):c.870C>T (p.Phe290=)]

NM_000488.4(SERPINC1):c.870C>T (p.Phe290=)

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.870C>T (p.Phe290=)

Other names:

NM_000488.4(SERPINC1):c.870C>T; p.Phe290=

HGVS:

NC_000001.11:g.173909835G>A
NG_012462.1:g.12544C>T
NM_000488.4:c.870C>TMANE SELECT
NM_001365052.2:c.726C>T
NM_001386302.1:c.993C>T
NM_001386303.1:c.951C>T
NM_001386304.1:c.849C>T
NM_001386305.1:c.813C>T
NM_001386306.1:c.654C>T
NP_000479.1:p.Phe290=
NP_000479.1:p.Phe290=
NP_001351981.1:p.Phe242=
NP_001373231.1:p.Phe331=
NP_001373232.1:p.Phe317=
NP_001373233.1:p.Phe283=
NP_001373234.1:p.Phe271=
NP_001373235.1:p.Phe218=
LRG_577t1:c.870C>T
LRG_577:g.12544C>T
LRG_577p1:p.Phe290=
NC_000001.10:g.173878973G>A
NM_000488.3:c.870C>T

Links:

dbSNP: rs370190321

NCBI 1000 Genomes Browser:

rs370190321

Molecular consequence:

NM_000488.4:c.870C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001365052.2:c.726C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386302.1:c.993C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386303.1:c.951C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386304.1:c.849C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386305.1:c.813C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001386306.1:c.654C>T - 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
SCV000351484	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000756585	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 27, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005367703	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen ACMG Specifications SERPINC1 V1.0.0)	Likely Benign (Aug 16, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000351484

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV000756585

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 27, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005367703

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)

Likely Benign
(Aug 16, 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

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

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000351484.3

#	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance 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, SCV000756585.6

#	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 Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005367703.1

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

Description

The c.870C>T (NM_000488.4) variant in SERPINC1 does not code for a different amino acid (p.Phe290=). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003730 (48/128676 alleles) in the European population, which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). SpliceAI predicts no splicing impact for this variant meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: 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 20, 2024

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