ClinVar Miner

Submissions for variant NM_000313.4(PROS1):c.1553C>T (p.Thr518Met)

gnomAD frequency: 0.00012  dbSNP: rs373336653
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851707 SCV000899525 uncertain significance Protein S deficiency disease 2019-02-01 criteria provided, single submitter research
Fulgent Genetics, Fulgent Genetics RCV002500995 SCV002788801 uncertain significance Thrombophilia due to protein S deficiency, autosomal dominant; Thrombophilia due to protein S deficiency, autosomal recessive 2021-08-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002536612 SCV003253816 uncertain significance Thrombophilia due to protein S deficiency, autosomal recessive 2023-07-25 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PROS1 protein function. ClinVar contains an entry for this variant (Variation ID: 627010). This missense change has been observed in individual(s) with clinical features of protein S deficiency (PMID: 31064749). This variant is present in population databases (rs373336653, gnomAD 0.02%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 518 of the PROS1 protein (p.Thr518Met).
PreventionGenetics, part of Exact Sciences RCV004753033 SCV005351292 uncertain significance PROS1-related disorder 2024-04-03 no assertion criteria provided clinical testing The PROS1 c.1553C>T variant is predicted to result in the amino acid substitution p.Thr518Met. This variant was reported in a patient with venous thromboembolism and another with a thrombotic anomaly (Table 2, Wu et al. 2022. PubMed ID: 35815065; Table S3, Downes et al 2019. PubMed ID: 31064749). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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