Submissions for variant NM_000488.4(SERPINC1):c.218C>T (p.Pro73Leu)

gnomAD frequency: 0.00092  dbSNP: rs121909551

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV000019627	SCV004037387	pathogenic	Hereditary antithrombin deficiency	2023-09-21	reviewed by expert panel	curation	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.
Illumina Laboratory Services, Illumina	RCV000019627	SCV000351487	pathogenic	Hereditary antithrombin deficiency	2017-04-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019627	SCV000756581	pathogenic	Hereditary antithrombin deficiency	2024-01-24	criteria provided, single submitter	clinical testing	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.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000019627	SCV000899323	likely pathogenic	Hereditary antithrombin deficiency	2019-02-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001090508	SCV001246102	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001090508	SCV001820746	likely pathogenic	not provided	2021-12-08	criteria provided, single submitter	clinical testing	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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000019627	SCV001983481	pathogenic	Hereditary antithrombin deficiency	2021-09-30	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000019627	SCV002019179	likely pathogenic	Hereditary antithrombin deficiency	2022-02-21	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000019627	SCV002515499	likely pathogenic	Hereditary antithrombin deficiency		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001090508	SCV002573725	likely pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing	PM1, PS3, PS4_Moderate
Fulgent Genetics, Fulgent Genetics	RCV000019627	SCV002810338	pathogenic	Hereditary antithrombin deficiency	2022-04-22	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Region Ostergotland	RCV000019627	SCV003925554	pathogenic	Hereditary antithrombin deficiency	2023-04-12	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001090508	SCV005198210	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019627	SCV005368365	pathogenic	Hereditary antithrombin deficiency	2024-09-02	criteria provided, single submitter	clinical testing	Criteria applied: PS4_VSTR,PP1_STR,PM1,PP3,PP4
OMIM	RCV000019627	SCV000039925	uncertain significance	Hereditary antithrombin deficiency	1992-03-01	flagged submission	literature only
CSER _CC_NCGL, University of Washington	RCV000019627	SCV000190626	likely benign	Hereditary antithrombin deficiency	2014-06-01	flagged submission	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000019627	SCV004099345	pathogenic	Hereditary antithrombin deficiency	2023-10-30	no assertion criteria provided	clinical testing