rs121909551

Positions:

chr1-173914743-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3PP4PS4PP1_StrongPM1

This summary comes from the ClinGen Evidence Repository: The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. 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: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210756/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13U:1B:1

Conservation

PhyloP100: 9.42

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]

SERPINC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS4

PM1

PP1

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4 linkuse as main transcript	c.218C>T	p.Pro73Leu	missense_variant	2/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4 linkuse as main transcript	c.218C>T	p.Pro73Leu	missense_variant	2/7	1	NM_000488.4	P1
SERPINC1	ENST00000494024.1 linkuse as main transcript	n.444C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000819

AC:

206

AN:

251456

Hom.:

AF XY:

0.000765

AC XY:

104

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00439

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00101

AC:

1470

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

690

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00380

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000840

AC:

128

AN:

152314

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000781

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Uncertain:1Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Pathogenic:10Uncertain:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SERPINC1 c.218C>T (p.Pro73Leu) missense variant is well described in the literature. Across a selection of the available literature, the p.Pro73Leu variant, which is also referred to as p.Pro41Leu, has been identified in a heterozygous state in four individuals diagnosed with antithrombin-III deficiency and with unspecified zygosity in 96 affected individuals (Chang et al. 1986; Molho-Sabatier et al. 1989; Puurunen et al. 2013; Feddersen et al. 2014). The p.Pro41Leu variant was absent from 106 controls, but is reported at a frequency of 0.00408 in the European (Finnish) population of the Exome Aggregation Consortium. Puurunen et al. (2013) suggest that the p.Pro73Leu variant is a founder variant in the Finnish population associated with type II hereditary antithrombin deficiency. The Pro73 residue is located at a heparin binding site. Bohdan et al. (2016) conducted a functional study to evaluate the effect of the p.Pro73Leu variant on binding affinity. The binding affinity between heparanase and antithrombin was greatly reduced in HEK-EBNA cells transfected with p.Pro73Leu variant plasmids compared to wildtype. Based on the collective evidence, the p.Pro73Leu variant is classified as pathogenic for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Sep 21, 2023	The c.218C>T (p.Pro73Leu) variant is reported at a POPMAX FAF of 0.0007473 in exomes in gnomAD v2.1.1 and at an FAF of 0.0006639 in genomes in gnomAD v3.1.1 in the non-Finnish European population. The frequency does not meet the threshold for PM2_Supporting. At least 30 probands with AT deficiency and several others from internal laboratory data are reported with AT tests on 2 independent samples, meeting criteria for PS4_VeryStrong and PP4. There at least 17 meioses out of 35 families meeting PP1_Strong (PMID:28300866). This missense variant has a REVEL score of 0.658 (threshold >0.6), meeting criteria for PP3, and is within a heparin binding site, meeting PM1. 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: PS4_VeryStrong, PP1_Strong, PM1, PP3, PP4. -
Uncertain significance, flagged submission	literature only	OMIM	Mar 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Likely benign, flagged submission	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Apr 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the SERPINC1 protein (p.Pro73Leu). This variant is present in population databases (rs121909551, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with type II antithrombin deficiency (PMID: 2794060, 3080419, 23910795, 24082793, 24956267, 26748602, 28317092). It is commonly reported in individuals of Finnish ancestry (PMID: 2794060, 3080419, 23910795, 24082793, 24956267, 26748602, 28317092). This variant is also known as Pro41Leu or AT Basel. ClinVar contains an entry for this variant (Variation ID: 18011). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINC1 protein function. Experimental studies have shown that this missense change affects SERPINC1 function (PMID: 2794060, 3080419, 24082793, 27322195). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2021	Variant summary: SERPINC1 c.218C>T (p.Pro73Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 251456 control chromosomes, predominatly in the Finnish and non-Finnish European subpopulations with a frequency of 0.0044 and 0.00089 respectively. The variant, c.218C>T (aka. Pro41Leu or AT Basel), is well known variant in the literature and has been reported in numerous individuals affected with Antithrombin III Deficiency (e.g. Chang_1986 , Molho-Sabatier_1989, Puurunen_2013, Bereczky_2021), and is considered to be a founder variant in the Finnish population (Puurunen_2013). Several of these publications reported significantly reduced antithrombin activity in carriers. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated reduced heparin binding properties (Martinez-Martinez_2012, Bohdan_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 23, 2021	PM1, PS3, PS4_Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2021	Published functional studies demonstrate defects in heparin binding properties (Martinez-Martinez, 2012; Bohdan et al., 2016); Reported previously as P41L or AT Basel using alternate nomenclature; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24196373, 24956267, 26748602, 22498748, 25637381, 3080419, 28317092, 2794060, 23910795, 27322195, 24082793, 29902631, 28300866, 30721820, 25837307, 31589614, 33614741) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

.;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.044

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.2

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.5

.;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

.;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

.;D

Vest4

0.92

MVP

0.96

MPC

1.1

ClinPred

0.089

GERP RS

5.7

Varity_R

0.50

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over