ClinVar Miner

Submissions for variant NM_000313.4(PROS1):c.1424G>T (p.Cys475Phe)

dbSNP: rs766692725
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003529470 SCV004293125 pathogenic Thrombophilia due to protein S deficiency, autosomal recessive 2023-04-19 criteria provided, single submitter clinical testing This variant disrupts the p.Cys475 amino acid residue in PROS1. Other variant(s) that disrupt this residue have been observed in individuals with PROS1-related conditions (PMID: 8765219, 28088608, 29748776), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt PROS1 protein function. This missense change has been observed in individuals with protein S deficiency (PMID: 18435454, 28088608). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 475 of the PROS1 protein (p.Cys475Phe). For these reasons, this variant has been classified as Pathogenic.

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