NM_000488.4(SERPINC1):c.830_831del (p.Glu277fs) AND Hereditary antithrombin deficiency

Germline classification:: Pathogenic (3 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:: RCV001235412.14

Allele description [Variation Report for NM_000488.4(SERPINC1):c.830_831del (p.Glu277fs)]

NM_000488.4(SERPINC1):c.830_831del (p.Glu277fs)

Gene:

SERPINC1:serpin family C member 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

1q25.1

Genomic location:

Preferred name:

NM_000488.4(SERPINC1):c.830_831del (p.Glu277fs)

Other names:

NM_001386306.1:c.614_615del

HGVS:

NC_000001.11:g.173909875TC[1]
NG_012462.1:g.12502AG[1]
NG_012462.1:g.12504_12505del
NM_000488.4:c.830_831delMANE SELECT
NM_001365052.2:c.686_687del
NM_001386302.1:c.953_954del
NM_001386303.1:c.911_912del
NM_001386304.1:c.809_810del
NM_001386305.1:c.773_774del
NM_001386306.1:c.614_615del
NP_000479.1:p.Glu277fs
NP_000479.1:p.Glu277fs
NP_001351981.1:p.Glu229fs
NP_001373231.1:p.Glu318fs
NP_001373232.1:p.Glu304fs
NP_001373233.1:p.Glu270fs
NP_001373234.1:p.Glu258fs
NP_001373235.1:p.Glu205fs
LRG_577t1:c.830_831del
LRG_577:g.12502AG[1]
LRG_577p1:p.Glu277fs
NC_000001.10:g.173879012_173879013del
NC_000001.10:g.173879013TC[1]
NC_000001.11:g.173909877_173909878del
NG_012462.1:g.12504_12505del
NM_000488.3:c.830_831del

Note:

NCBI staff provided an HGVS expression for this deletion from the gel in Figure 2 of the paper by Grundy et al., 1991 (PubMed 1868237).

Protein change:

E205fs

Links:

OMIM: 107300.0029; dbSNP: rs1657694750

NCBI 1000 Genomes Browser:

rs1657694750

Molecular consequence:

NM_000488.4:c.830_831del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365052.2:c.686_687del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386302.1:c.953_954del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386303.1:c.911_912del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386304.1:c.809_810del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386305.1:c.773_774del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386306.1:c.614_615del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Gm10237 predicted gene 10237 [Mus musculus]
Gm10237 predicted gene 10237 [Mus musculus]
Gene ID:100043217

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039939	OMIM	no assertion criteria provided	Pathogenic (Aug 15, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001408095	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21264449, 1868237, 28492532
SCV004037395	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

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000039939

OMIM

no assertion criteria provided

Pathogenic
(Aug 15, 1991)

germline

literature only

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

SCV001408095

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004037395

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

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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Molecular basis of antithrombin deficiency.

Luxembourg B, Delev D, Geisen C, Spannagl M, Krause M, Miesbach W, Heller C, Bergmann F, Schmeink U, Grossmann R, Lindhoff-Last E, Seifried E, Oldenburg J, Pavlova A.

Thromb Haemost. 2011 Apr;105(4):635-46. doi: 10.1160/TH10-08-0538. Epub 2011 Jan 25.

PubMed [citation]

PMID:: 21264449

Recurrent deletion in the human antithrombin III gene.

Grundy CB, Thomas F, Millar DS, Krawczak M, Melissari E, Lindo V, Moffat E, Kakkar VV, Cooper DN.

Blood. 1991 Aug 15;78(4):1027-32.

PubMed [citation]

PMID:: 1868237

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000039939.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Grundy et al. (1991) identified 2 patients, each from unrelated families segregating AT-III deficiency and a history of thrombosis (613118), who were heterozygous for different frameshift mutations involving the same GAG codon (glu245) in exon 4 of the AT3 gene. One patient had a heterozygous deletion of the A nucleotide (107300.0028), whereas the second had a heterozygous deletion of an A and a G. Grundy et al. (1991) pointed out that the deletion-prone glu245 codon is located within a GAGAG motif that is effectively a short overlapping direct repeat. In addition, a short inverted repeat flanked the site of deletion. They pointed to similar deletion hotspots in the F8, HPRT, HBA2, and HBB genes and pointed out common characteristics of these hotspots.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001408095.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SERPINC1 are known to be pathogenic (PMID: 21264449). This variant has been observed in several individuals affected with Antithrombin deficiency (PMID: 1868237). This variant is also known as p.Glu245fs* in the literature This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu277Valfs*20) in the SERPINC1 gene. It is expected to result in an absent or disrupted protein product.

#	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, SCV004037395.1

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

Description

The variant SERPINC1 p.Glu277ValfsTer20 is predicted to lead to a loss of function by nonsense mediated mRNA decay (NMD) with the being exon present in biologically relevant transcripts. The variant has been reported in 5 individuals in the literature (PMID: 33220012, 30721820, 1868237, 33725558) meeting the SERPINC1 phenotype criteria; however only 1 of them was reported with repeat AT testing meeting PP4 and PS4_Moderate criteria. To date, the variant has not been reported in the general population (gnomAD v2.1.1 and v3.1) found in neither the genomes nor exomes meeting PM2_Supporting. The variant has been reported in 18 segregations across 3 families in the literature meeting PP1_Strong (PMIDs: 33220012, 1868237, 33725558). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PVS1, PP1_strong, PS4_Moderate, PP4, PM2_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

Last Updated: Nov 3, 2024

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