ClinVar Miner

Submissions for variant NM_000488.4(SERPINC1):c.1306G>A (p.Ala436Thr)

dbSNP: rs121909546
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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 RCV000019619 SCV005367700 likely pathogenic Hereditary antithrombin deficiency 2024-08-16 reviewed by expert panel curation The c.1306G>A (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 436 (p.Ala436Thr). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL with either a family history of antithrombin activity levels of < 0.8 IU/mL or an abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function. One more proband is reported with antithrombin activity levels of < 0.8 IU/mL but no repeat testing or family history is specified so 0.5 point is awarded (PS4_Moderate; PMID:3055413, 1469094). The variant has been reported to segregate with autosomal dominant antithrombin deficiency in 11 affected meioses from one family (PP1_Moderate; PMIDs:1469094, 3055413). The computational predictor REVEL gives a score of 0.778, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1_Moderate, PM2_Supporting, PS4_Moderate, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV000019619 SCV000756580 pathogenic Hereditary antithrombin deficiency 2018-10-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies using both patient cells and transfected cell lines have shown that cells carrying this missense variant demonstrate reduced antithrombin activity and antigen levels (PMID: 1469094, 16620552). This variant has been reported to segregate with antithrombin deficiency in several families (PMID: 1469094, 16620552). ClinVar contains an entry for this variant (Variation ID: 18003). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 436 of the SERPINC1 protein (p.Ala436Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
OMIM RCV000019619 SCV000039917 pathogenic Hereditary antithrombin deficiency 1988-06-16 no assertion criteria provided literature only

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