GeneBe

1-173904011-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_ModeratePM5PP3PP4PM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID:27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210762/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SERPINC1
NM_000488.4 missense

Scores

9
8
2

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 7.20
Variant links:
Genes affected
SERPINC1 (HGNC:775): (serpin family C member 1) The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SERPINC1NM_000488.4 linkc.1273C>T p.Arg425Cys missense_variant Exon 7 of 7 ENST00000367698.4 NP_000479.1 P01008A0A024R944

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SERPINC1ENST00000367698.4 linkc.1273C>T p.Arg425Cys missense_variant Exon 7 of 7 1 NM_000488.4 ENSP00000356671.3 P01008

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251344
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:3
Aug 30, 1988
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 24, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine with cysteine at codon 425 of the SERPINC1 protein (p.Arg425Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121909554, ExAC 0.01%). This variant has been observed in several individuals with antithrombin deficiency and segregates with disease in at least one family (PMID: 22481271, 27098529, 3179448, 3179448, 4049307). This variant is also known as R393C, Arg393Cys, and Antithrombin III Northwick Park in the literature. ClinVar contains an entry for this variant (Variation ID: 18016). This variant has been reported to affect SERPINC1 protein function (PMID: 22481271). This variant disrupts the p.Arg425 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 22481271, 28317092), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Aug 16, 2024
Clingen Thrombosis Variant Curation Expert Panel, ClinGen
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.1273C>T variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 425 (p.Arg425Cys). This variant is seen with a total MAF of 0.0000006195, which meets PM2_Supporting. At least one patient with this variant displayed an antithrombin activity level of < 0.8 IU/mL on repeated independent samples, which is highly specific for hereditary antithrombin deficiency (PP4, PMID: 27098529). This variant has been reported in eight more probands with an antithrombin activity level of < 0.8 IU/mL, but not all of them had testing performed on repeated independent samples, crossed immunoelectrophoresis demonstrating an abnormal result or a family history (5.5 points awarded, PS4; PMIDs:22398878, 28300866, 23910795, 4049307, 22481271, 27098529). The variant has been reported to segregate with hereditary antithrombin deficiency in four affected family members, aside from the proband, from one family (PP1_Moderate; PMID:4049307). Another missense variant c.1274G>A (p.Arg425His) (ClinVarID:18019) in the same codon has been classified as pathogenic for hereditary antithrombin deficiency by the ClinGen Thrombosis VCEP (PM5). The computational predictor REVEL gives a score of 0.806, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PS4, PP1_Moderate, PM5, PM2_Supporting, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
.;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Uncertain
2.3
.;M
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.8
.;D
REVEL
Pathogenic
0.86
Sift
Benign
0.27
.;T
Sift4G
Uncertain
0.0020
D;T
Polyphen
1.0
.;D
Vest4
0.96
MVP
0.92
MPC
1.3
ClinPred
0.98
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121909554; hg19: chr1-173873149; API