NM_000488.4(SERPINC1):c.1366G>C (p.Gly456Arg) AND Hereditary antithrombin deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 2, 2023
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:: RCV002664191.4

Allele description [Variation Report for NM_000488.4(SERPINC1):c.1366G>C (p.Gly456Arg)]

NM_000488.4(SERPINC1):c.1366G>C (p.Gly456Arg)

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.1366G>C (p.Gly456Arg)

HGVS:

NC_000001.11:g.173903918C>G
NG_012462.1:g.18461G>C
NM_000488.4:c.1366G>CMANE SELECT
NM_001365052.2:c.1222G>C
NM_001386302.1:c.1489G>C
NM_001386303.1:c.1447G>C
NM_001386304.1:c.1345G>C
NM_001386305.1:c.1309G>C
NM_001386306.1:c.1150G>C
NP_000479.1:p.Gly456Arg
NP_000479.1:p.Gly456Arg
NP_001351981.1:p.Gly408Arg
NP_001373231.1:p.Gly497Arg
NP_001373232.1:p.Gly483Arg
NP_001373233.1:p.Gly449Arg
NP_001373234.1:p.Gly437Arg
NP_001373235.1:p.Gly384Arg
LRG_577t1:c.1366G>C
LRG_577:g.18461G>C
LRG_577p1:p.Gly456Arg
NC_000001.10:g.173873056C>G
NM_000488.3:c.1366G>C

Protein change:

G384R

Molecular consequence:

NM_000488.4:c.1366G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365052.2:c.1222G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386302.1:c.1489G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386303.1:c.1447G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386304.1:c.1345G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386305.1:c.1309G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386306.1:c.1150G>C - 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
SCV003523920	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8274732, 28492532
SCV004099004	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003523920

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 19, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004099004

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 2, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Antithrombin-Gly 424 Arg: a novel point mutation responsible for type 1 antithrombin deficiency and neonatal thrombosis.

Jochmans K, Lissens W, Vervoort R, Peeters S, De Waele M, Liebaers I.

Blood. 1994 Jan 1;83(1):146-51.

PubMed [citation]

PMID:: 8274732

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003523920.2

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 456 of the SERPINC1 protein (p.Gly456Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with antithrombin deficiency (PMID: 8274732). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004099004.1

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

Description

PS3, PM1, PM2, Pp1, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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