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NM_000313.4(PROS1):c.1501T>C (p.Ser501Pro) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Jul 12, 2022
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001358591.12

Allele description [Variation Report for NM_000313.4(PROS1):c.1501T>C (p.Ser501Pro)]

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

Gene:
PROS1:protein S [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q11.1
Genomic location:
Preferred name:
NM_000313.4(PROS1):c.1501T>C (p.Ser501Pro)
Other names:
S460P
HGVS:
  • NC_000003.12:g.93879306A>G
  • NG_009813.1:g.99785T>C
  • NM_000313.4:c.1501T>CMANE SELECT
  • NM_001314077.2:c.1597T>C
  • NP_000304.2:p.Ser501Pro
  • NP_000304.2:p.Ser501Pro
  • NP_001301006.1:p.Ser533Pro
  • LRG_572t1:c.1501T>C
  • LRG_572:g.99785T>C
  • LRG_572p1:p.Ser501Pro
  • NC_000003.11:g.93598150A>G
  • NM_000313.3:c.1501T>C
  • P07225:p.Ser501Pro
Protein change:
S501P; SER460PRO
Links:
UniProtKB: P07225#VAR_005568; OMIM: 176880.0001; dbSNP: rs121918472
NCBI 1000 Genomes Browser:
rs121918472
Molecular consequence:
  • NM_000313.4:c.1501T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001314077.2:c.1597T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
7

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001554373Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

SCV001814825GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Uncertain significance
(Oct 15, 2020) 		germlineclinical testing

Citation Link,

SCV004227334Mayo Clinic Laboratories, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jul 12, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown7not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554373.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV001814825.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004227334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided7not providednot providedclinical testing PubMed (1)

Description

PP5, PS3, PS4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided7not providednot providednot provided

Last Updated: Nov 10, 2024