ClinVar Miner

Submissions for variant NM_000488.3(SERPINC1):c.236G>A (p.Arg79His) (rs121909552)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148881 SCV000190625 likely benign Antithrombin deficiency 2014-06-01 no assertion criteria provided research
Illumina Clinical Services Laboratory,Illumina RCV000019630 SCV000915376 uncertain significance Reduced antithrombin III activity 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 likely pathogenic Reduced antithrombin III activity 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 79 of the SERPINC1 protein (p.Arg79His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121909552, ExAC 0.01%). This variant has been observed in several individuals and families with antithrombin deficiency (PMID: 2615648, 26748602, 29153735, 25837307, 21264449, 28607330, 3567355, 7981186). This variant is also known as R47H, Arg47His, AT Padua I, or AT Rouen I in the literature. ClinVar contains an entry for this variant (Variation ID: 18014). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 observed in individuals with SERPINC1-related conditions (PMID: 21325262, 28300866, 6582486, 24162787), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000019630 SCV000039928 pathogenic Reduced antithrombin III activity 1994-12-01 no assertion criteria provided literature only

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