ClinVar Miner

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

gnomAD frequency: 0.00018  dbSNP: rs121909552
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Total submissions: 11
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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

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