ClinVar Miner

Submissions for variant NM_000488.4(SERPINC1):c.1274G>A (p.Arg425His)

dbSNP: rs121909549
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clingen Thrombosis Variant Curation Expert Panel, ClinGen RCV000019635 SCV004037397 pathogenic Hereditary antithrombin deficiency 2023-09-21 reviewed by expert panel curation The c.1274G>A (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 425 (p.Arg425His; legacy nomenclature p.R393H aka Antithrombin Glasgow). The computational predictor REVEL gives a score of 0.806, which is above the threshold of >0.6 and provides evidence that correlates with impact to SERPINC1 function, meeting criteria for PP3. This variant is at extremely low frequency (Total: 0.000003979, European (non-Finnish): 0.000008798) in gnomAD v2.1.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting (MAF <2.0 X 10-5). This variant has been reported in at least 16 probands in the literature with AT deficiency meeting PP4 and PS4_VeryStrong (PMID: 26134363; 27766527; 28607330; 28300866; 3179448). Additionally, this variant has been report in at least 4 meioses across 14 families meeting PP1_Moderate. In summary, based on the evidence available at this time, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PP1_Moderate, PP3, PP4, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000019635 SCV001577970 pathogenic Hereditary antithrombin deficiency 2020-01-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg425Cys amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22481271, 27098529, 3179448, 4049307). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect SERPINC1 protein function (PMID: 22481271). This variant has been observed in individual(s) with antithrombin III deficiency (PMID: 3179448, 22481271, 28317092, 28607330, Invitae). This variant is also known as Arg393His and ATIII Glasgow in the literature. ClinVar contains an entry for this variant (Variation ID: 18019). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 425 of the SERPINC1 protein (p.Arg425His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
OMIM RCV000019635 SCV000039933 pathogenic Hereditary antithrombin deficiency 1989-10-01 no assertion criteria provided literature only

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