ClinVar Miner

Submissions for variant NM_000313.3(PROS1):c.1501T>C (p.Ser501Pro) (rs121918472)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755688 SCV000883101 uncertain significance Protein S deficiency 2018-11-21 criteria provided, single submitter clinical testing
Invitae RCV000205145 SCV000260947 uncertain significance Thrombophilia due to protein S deficiency, autosomal recessive 2018-06-07 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 501 of the PROS1 protein (p.Ser501Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs121918472, ExAC 0.3%). This variant is known as the Heerlen variant, also reported as Ser460Pro. This variant has been reported in several individuals with type III protein S deficiency and it segregates with disease in multiple families but some carriers are unaffected (PMID: 7579448, 1547381, 12960605, 24119292). The pathogenicity of this variant is much debated in the literature with reports that argue for a pathogenic classification, a benign polymorphism as well as a modifier that works in synergy with other genetic factors. ClinVar contains an entry for this variant (Variation ID: 13316). This variant has been classified as a polymorphism in some reports because it is present at a similar frequency in controls as well as affected individuals (PMID: 2143091, 24014240) and it has been reported in unaffected family members (PMID: 15147381). In contrast, several studies report a statistically significant increase in the Heerlen allele frequency in individuals with low protein S levels and/or venous thrombosis (PMID: 8765219, 7579448, 10669162, 28374852). In addition, individuals homozygous for Heerlen have been reported to have lower protein S levels and a more severe type I form compared to individuals that are heterozygous (PMID: 10887114, 10669162). Finally, several reports suggest that the Heerlen variant shows synergy with other genetic risks for thrombosis such as Factor V Leiden and/or APC (activated protein C) variants (PMID: 8765219, 10669162, 20880255, 24365770). One functional study reports a synergy with Factor V Leiden mutation and a reduced capacity for the Heerlen variant to act as a co-factor for APC (PMID: 10887114). In conclusion, there is evidence to support increased risk for protein S deficiency in heterozygous individuals and homozygous individuals show a more severe deficiency, although this variant has also been reported in unaffected family members and in control individuals. There is also evidence to support that the Heerlen variant alone has a mild effect but acts in synergy with other genetic factors. Because there is support for both a pro-pathogenic and a pro-benign effect, this sequence change has been classified as Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000246742 SCV000966743 uncertain significance not specified 2019-02-04 criteria provided, single submitter clinical testing The p.Ser501Pro variant in PROS1 (also reported as p.Ser460Pro or PS Heerlen) ha s been identified in >20 individuals with protein S deficiency type III (Duchemi n 1995, Espinosa-Parrilla 2000, Beachamp 2004, ten Kate 2008, Varvenne 2011, Mul der 2012, Wypasek 2014). While the variant segregated with protein S deficiency in >10 affected family members (Duchemin 1995, Espinosa-Parrilla 2000, Beachamp 2004, ten Kate 2008), there were also multiple individuals in these families who had protein S deficiency but were negative for the p.Ser501Pro variant (Espinos a-Parrilla 2000, ten Kate 2008). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this info rmation is not predictive enough to rule out pathogenicity. In vivo and in vitro functional studies provide some evidence that this variant may impact protein S function (Duchemin 1995, Denis 2005); however, these types of assays may not ac curately represent biological function. This variant has also been identified in individuals with normal protein S levels (Espinosa-Parrilla 2000, Beauchamp 200 4, ten Kate 2008) and in 0.33% (425/129150) of European chromosomes in gnomAD (h ttp://gnomad.broadinstitute.org). The variant is also present in ClinVar with co nflicting interpretations (Variation ID: 13316). While one meta-analysis has rep orted an odds ratio of 4-10 for venous thrombosis in French individuals who are heterozygous for this variant (Suchon 2017), this result has not been replicated . Furthermore, other studies find no association between this or other PROS1 var iants and the risk for thrombosis (Alhenc-Gelas 2010, Pintao 2013). In summary, given the conflicting data regarding the impact of this variant on plasma protei n S levels and risk for thrombosis, the clinical significance of the p.Ser501Pro variant is uncertain. ACMG/AMP criteria applied: PP1_Strong, PS3_Supporting, BS 4, BS1_Supporting, BP4.
OMIM RCV000014244 SCV000034492 pathogenic Protein S Heerlen 2004-06-01 no assertion criteria provided literature only
PreventionGenetics RCV000246742 SCV000303562 likely benign not specified criteria provided, single submitter clinical testing

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