ClinVar Miner

Submissions for variant NM_000488.3(SERPINC1):c.218C>T (p.Pro73Leu) (rs121909551)

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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 RCV000148882 SCV000190626 likely benign Antithrombin deficiency 2014-06-01 no assertion criteria provided research
Illumina Clinical Services Laboratory,Illumina RCV000019627 SCV000351487 pathogenic Reduced antithrombin III activity 2017-04-27 criteria provided, single submitter clinical testing The SERPINC1 c.218C>T (p.Pro73Leu) missense variant is well described in the literature. Across a selection of the available literature, the p.Pro73Leu variant, which is also referred to as p.Pro41Leu, has been identified in a heterozygous state in four individuals diagnosed with antithrombin-III deficiency and with unspecified zygosity in 96 affected individuals (Chang et al. 1986; Molho-Sabatier et al. 1989; Puurunen et al. 2013; Feddersen et al. 2014). The p.Pro41Leu variant was absent from 106 controls, but is reported at a frequency of 0.00408 in the European (Finnish) population of the Exome Aggregation Consortium. Puurunen et al. (2013) suggest that the p.Pro73Leu variant is a founder variant in the Finnish population associated with type II hereditary antithrombin deficiency. The Pro73 residue is located at a heparin binding site. Bohdan et al. (2016) conducted a functional study to evaluate the effect of the p.Pro73Leu variant on binding affinity. The binding affinity between heparanase and antithrombin was greatly reduced in HEK-EBNA cells transfected with p.Pro73Leu variant plasmids compared to wildtype. Based on the collective evidence, the p.Pro73Leu variant is classified as pathogenic for antithrombin-III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000019627 SCV000756581 pathogenic Reduced antithrombin III activity 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 73 of the SERPINC1 protein (p.Pro73Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs121909551, ExAC 0.4%). This variant has been reported in numerous individuals with type II antithrombin deficiency (PMID: 3080419, 28317092, 24956267, 24082793, 26748602, 2794060). This variant has been reported as a founder mutation in the Finnish population (PMID: 23910795). This variant is also known as Pro41Leu or AT Basel in the literature. ClinVar contains an entry for this variant (Variation ID: 18011). Diagnostic assays have shown that individuals carrying this variant have significantly reduced antithrombin activity (PMID: 3080419, 24082793, 27322195, 2794060). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019627 SCV000039925 uncertain significance Reduced antithrombin III activity 1992-03-01 no assertion criteria provided literature only

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