ClinVar Miner

Submissions for variant NM_000312.4(PROC):c.169C>T (p.Arg57Trp)

gnomAD frequency: 0.00002  dbSNP: rs757583846
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168170 SCV000218832 pathogenic Thrombophilia due to protein C deficiency, autosomal dominant 2023-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 57 of the PROC protein (p.Arg57Trp). This variant is present in population databases (rs757583846, gnomAD 0.006%). This missense change has been observed in individual(s) with protein C deficiency (PMID: 7482420, 7792728, 8446940, 8499568, 14642106). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1432C>T, Arg15Trp, and C5498T. ClinVar contains an entry for this variant (Variation ID: 188230). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg57 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1464619, 1498334, 1771629, 8477066, 8505327). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000490205 SCV000577736 likely pathogenic not provided 2015-06-08 criteria provided, single submitter clinical testing The R57W variant in the PROC gene has been reported previously in association with protein C deficiency (Zhou et al., 2003 [article in Chinese]; Stenson et al., 2014). The R57W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R57W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in association with protein C deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R57W variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.
MGZ Medical Genetics Center RCV000168170 SCV002579673 likely pathogenic Thrombophilia due to protein C deficiency, autosomal dominant 2021-11-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002498834 SCV002813713 likely pathogenic Thrombophilia due to protein C deficiency, autosomal recessive; Thrombophilia due to protein C deficiency, autosomal dominant 2021-11-16 criteria provided, single submitter clinical testing

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