Submissions for variant NM_000488.4(SERPINC1):c.236G>A (p.Arg79His)

gnomAD frequency: 0.00018  dbSNP: rs121909552

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen	RCV000019630	SCV004037392	pathogenic	Hereditary antithrombin deficiency	2023-09-21	reviewed by expert panel	curation	The c.236G>A (p.Arg79His) variant is reported at an FAF of 0.0002303 and MAF of 0.0003380 (23/68044 alleles) in the non-Finnish European population in gnomAD v3.1.1 meeting BS1 criteria of MAF >0.0002. However, this variant is an established founder variant known as AT Padua I making it ineligible for the BS1 rule application. It has a REVEL score of 0.702, and meets PP3. At least 23 individuals with AT deficiency meeting the SERPINC1 phenotype criteria (other cases are reported but do not meet criteria) are reported in the literature meeting PS4_Very Strong and PP4. Additionally, 9 meioses have been reported across 16 families meeting PP1_Strong. In summary, this variant reaches a classification of pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Strong, PM1, PP3, PP4.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000019630	SCV000899615	uncertain significance	Hereditary antithrombin deficiency	2019-02-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000019630	SCV000915376	uncertain significance	Hereditary antithrombin deficiency	2017-05-03	criteria provided, single submitter	clinical testing	The SERPINC1 c.236G>A (p.Arg79His) missense variant has been identified in a heterozygous state in five patients with antithrombin-III (AT) deficiency (Orlando et al. 2015). Gindele et al. (2016) also reported this variant in 6.7% of patients with type II heparin binding site deficiency (HBS). In the Orlando et al. (2015) study, two patients each also had arterial events and venous thrombotic events, respectively. However, another study indicated that endogenous thrombin potential was not increased in carriers of the p.Arg79His variant, thereby suggesting that this variant is associated with a low risk of venous thromboembolism (Alhenc-Gelas et al. 2010). In addition, using multiple commercially available methods, AT activity was measured in the five patients from the Orlando et al. (2015) study and activity was decreased in some cases, but some of these methods did not show decreased activity. Another variant at this amino acid position, p.Arg79Cys, has also been observed in patients (Orlando et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg79His variant is classified as a variant of unknown significance but suspicious for pathogenicity for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000019630	SCV000963796	pathogenic	Hereditary antithrombin deficiency	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 79 of the SERPINC1 protein (p.Arg79His). This variant is present in population databases (rs121909552, gnomAD 0.02%). This missense change has been observed in individuals with antithrombin deficiency (PMID: 2363123, 2615648, 3567355, 7981186, 21264449, 25837307, 26748602, 28607330, 29153735, 31885188, 35626216). This variant is also known as R47H, Arg47His, AT Padua I, AT Rouen I, or AT III Bligny. ClinVar contains an entry for this variant (Variation ID: 18014). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINC1 protein function with a negative predictive value of 95%. This variant disrupts the p.Arg79 (also known as p.Arg47) amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 6582486, 21325262, 24162787, 28300866). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000019630	SCV002019180	likely pathogenic	Hereditary antithrombin deficiency	2022-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002054451	SCV002496959	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	SERPINC1: PS1, PM1, PP1, PP4, PS3:Supporting, PS4:Supporting
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000019630	SCV002569222	likely pathogenic	Hereditary antithrombin deficiency		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002054451	SCV002573724	likely pathogenic	not provided	2021-08-16	criteria provided, single submitter	clinical testing	PS4_Moderate, PM1, PM2, PM5, PP5
OMIM	RCV000019630	SCV000039928	pathogenic	Hereditary antithrombin deficiency	1994-12-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000019630	SCV000190625	likely benign	Hereditary antithrombin deficiency	2014-06-01	no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000019630	SCV004041731	pathogenic	Hereditary antithrombin deficiency	2023-10-09	no assertion criteria provided	clinical testing