Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clingen Thrombosis Variant Curation Expert Panel, |
RCV000810125 | SCV005061622 | likely pathogenic | Hereditary antithrombin deficiency | 2024-05-09 | reviewed by expert panel | curation | The NM_000488.4:c.449A>C variant in SERPINC1 is a missense variant predicted to cause substitution of Glutamine by Proline at amino acid 150 (p.Gln150Pro). This variant is also known as antithrombin Vienna (Legacy nomenclature: Gln118Pro) in the literature. At least one patient with this variant displayed AT deficiency (type II- HBD) which is highly specific for SERPINC1 (PP4, PMID: 7734360). The computational predictor REVEL gives a score of 0.865, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 gene function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008791 (1/113750 alleles) in the non-Finnish European population, which is lower than the ClinGen Thrombosis VCEP threshold (<0.00002 ) for PM2_Supporting, meeting this criterion. In summary, this variant meets the criteria to be classified as a pathogenic for antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP. (Specifications version 1.0.0; date of approval: 7/17/2023). |
| Labcorp Genetics |
RCV000810125 | SCV000950314 | uncertain significance | Hereditary antithrombin deficiency | 2018-10-03 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals affected with type II antithrombin (AT) deficiency (PMID: 11192751, 25837307, 28300866). It has also been observed to segregate with AT deficiency without clinical symptoms in a family (PMID: 7734360). This variant is also known as 5349A>C, Gln118Pro in the literature. This variant is present in population databases (rs765445413, ExAC 0.001%). This sequence change replaces glutamine with proline at codon 150 of the SERPINC1 protein (p.Gln150Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. |
| Mayo Clinic Laboratories, |
RCV002284206 | SCV002573722 | likely pathogenic | not provided | 2022-01-13 | criteria provided, single submitter | clinical testing | PP1, PP3, PM2, PS4_Moderate |
| Fulgent Genetics, |
RCV000810125 | SCV002813329 | uncertain significance | Hereditary antithrombin deficiency | 2021-09-24 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004754569 | SCV005346917 | likely pathogenic | SERPINC1-related disorder | 2024-07-23 | no assertion criteria provided | clinical testing | The SERPINC1 c.449A>C variant is predicted to result in the amino acid substitution p.Gln150Pro. This variant has been reported in the heterozygous state in individuals with antithrombin deficiency (Chowdhury et al. 1995. PubMed ID: 7734360; Orlando et al. 2015. PubMed ID: 25837307; Alhenc-Gelas et al. 2017. PubMed ID: 28300866). It has also been described in an individual with thrombosis who also carried a second SERPINC1 variant (Provazníková et al. 2020. PubMed ID: 32151802). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. |