Submissions for variant NM_000313.4(PROS1):c.1501T>C (p.Ser501Pro)

dbSNP: rs121918472

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205145	SCV000260947	uncertain significance	Thrombophilia due to protein S deficiency, autosomal recessive	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 501 of the PROS1 protein (p.Ser501Pro). This variant is present in population databases (rs121918472, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. 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. It has also been observed to segregate with disease in related individuals. 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). ClinVar contains an entry for this variant (Variation ID: 13316). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV000246742	SCV000303562	likely benign	not specified		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755688	SCV000883101	uncertain significance	Thrombophilia due to protein S deficiency, autosomal dominant	2018-11-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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) has been identified in >20 individuals with protein S deficiency type III (Duchemin 1995, Espinosa-Parrilla 2000, Beachamp 2004, ten Kate 2008, Varvenne 2011, Mulder 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 (Espinosa-Parrilla 2000, ten Kate 2008). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information 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 accurately represent biological function. This variant has also been identified in individuals with normal protein S levels (Espinosa-Parrilla 2000, Beauchamp 2004, ten Kate 2008) and in 0.33% (425/129150) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org). The variant is also present in ClinVar with conflicting interpretations (Variation ID: 13316). While one meta-analysis has reported 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 variants and the risk for thrombosis (Alhenc-Gelas 2010, Pintao 2013). In summary, given the conflicting data regarding the impact of this variant on plasma protein S levels and risk for thrombosis, the clinical significance of the p.Ser501Pro variant is uncertain. ACMG/AMP criteria applied: PP1_Strong, PS3_Supporting, BS4, BS1_Supporting, BP4.
Illumina Laboratory Services, Illumina	RCV000755688	SCV001306866	uncertain significance	Thrombophilia due to protein S deficiency, autosomal dominant	2018-02-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001358591	SCV001814825	uncertain significance	not provided	2020-10-15	criteria provided, single submitter	clinical testing	Identified in multiple heterozygous individuals with protein S deficiency and some of these individuals have a history of thrombosis (Duchemin et al., 1995; Borgel et al., 1996; Espinosa-Parrilla et al., 2000; Labrouche et al., 2003; Beauchamp et al., 2004; ten Kate et al., 2008; Suchon et al., 2017; Wypasek et al., 2017); Reported in at least one asymptomatic homozygous individual with type I protein S deficiency and protein S levels lower than heterozygous individuals (Espinosa-Parilla et al., 2000; Giri et al., 2000); Segregates with protein S deficiency in multiple relatives from unrelated families; however, it was absent from some relatives with protein S deficiency, and it has been found in relatives without protein S deficiency, as well as in unrelated control individuals (Duchemin et al., 1995; Espinosa-Parrilla et al., 1997; Beauchamp et al., 2004; ten Kate et al., 2008); Several individuals with a history of thrombotic events who harbored this variant also harbored additional variants, including factor V Leiden (Borgel et al., 1996; Espinosa-Parrilla et al., 2000; Wypasek et al., 2014; Bruwer et al., 2016); Although at least one early study found no significant difference in the frequency of this variant in individuals with thrombophilia versus controls, a subsequent larger study did find an increased frequency of this variant in individuals with venous thrombosis, with an estimated odds ratio of 6.57 (Bertina et al., 1990; Suchon et al., 2017); Published in vitro assays demonstrate that the S501P variant is associated with faster clearance than wild-type protein S (Denis et al., 2005); An additional functional study suggests that S501P displays deficient APC-cofactor activity in the degradation of factor V Leiden and that there may be synergistic effects between thrombophilic risk factors, while another study reports that S501P has no impact on APC-cofactor and APC-independent coagulation activities (Giri et al., 2000; Koenen et al., 2004); In silico analysis supports that this missense variant does not alter protein structure/function; Also described as the Heerlen allele/polymorphism or S460P using alternate nomenclature; This variant is associated with the following publications: (PMID: 9108398, 15175796, 10887114, 18841302, 24119292, 29883906, 27838551, 18435454, 24365770, 24014240, 12960605, 8765219, 20880255, 31019283, 7579448, 10669162, 28607330, 28374852, 2143091, 15147381, 16100035, 21764424, 22273984)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000755688	SCV002500909	likely pathogenic	Thrombophilia due to protein S deficiency, autosomal dominant		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447474	SCV004175577	uncertain significance	Hereditary thrombophilia due to congenital protein S deficiency	2021-09-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001358591	SCV004227334	pathogenic	not provided	2024-09-18	criteria provided, single submitter	clinical testing	PP5, PS3, PS4
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814905	SCV005069553	uncertain significance	Optic atrophy	2023-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814904	SCV005073452	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000014244	SCV000034492	pathogenic	Protein S Heerlen	2004-06-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358591	SCV001554373	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PROS1 p.Ser533Pro variant, also commonly referred to as the Heerlen variant, was identified in 141 of 11096 proband chromosomes (frequency: 0.0127) from individuals or families with venous thrombosis or Protein S deficiency (Labrouche_2003_PMID:12960605, Bertina_1990_PMID:2143091, Suchon_2017_PMID:28374852, Borgel_1996_PMID:8765219).The variant was identified in dbSNP (ID: rs121918472) and ClinVar (classified as a VUS by Invitae and Equipe Genetique des Anomalies du Developpement, Université de Bourgogne in 2018 and as likely benign by PreventionGenetics). The variant was identified in control databases in 570 of 282838 chromosomes (1 homozygous) at a frequency of 0.002015 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 425 of 129150 chromosomes (freq: 0.003291), European (Finnish) in 37 of 25124 chromosomes (freq: 0.001473), Latino in 51 of 35432 chromosomes (freq: 0.001439), Other in 10 of 7226 chromosomes (freq: 0.001384), South Asian in 35 of 30616 chromosomes (freq: 0.001143), African in 9 of 24970 chromosomes (freq: 0.00036), Ashkenazi Jewish in 2 of 10368 chromosomes (freq: 0.000193), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). Evidence for this variant’s role in protein S (encoded by PROS1) deficiency and venous thrombosis is conflicting. One study identified that the variant segregated with protein S deficiency in seven families, though a few carriers were unaffected (Duchemin_1995_PMID:7579448). Other studies have also found that the variant segregates with protein S deficiency, and that individuals homozygous for the Heerlen variant have been reported to have lower protein S levels and a more severe type I form compared to individuals that are heterozygous (Espinosa-Parilla_2000_PMID:10669162). Several studies report a statistically significant increase in the Heerlen allele frequency in individuals with low protein S levels and/or venous thrombosis (Borgel_1996_PMID:8765219, Duchemin_1995_PMID:7579448, Suchon_2017_PMID:28374852). However, other studies have identified the variant at a similar frequency in controls as well as affected individuals (PMID: Bertina_1990_2143091, Pintao_2013_PMID:24014240). 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 (Giri_2010_PMID:10887114). Therefore it is unclear at this time if the Heerlen variant is pathogenic for venous thrombosis or Protein S deficiency, however it may contribute risk in conjuction with other genetic factors. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ser533 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000755688	SCV004041785	uncertain significance	Thrombophilia due to protein S deficiency, autosomal dominant	2023-10-09	no assertion criteria provided	clinical testing