3-93879306-A-G

Variant names:

• chr3-93879306-A-G
• rs121918472
• NM_000313.4:c.1501T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BS1_Supporting BS2

The NM_000313.4(PROS1):​c.1501T>C​(p.Ser501Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,613,946 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S501A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: PROS1 NM_000313.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:10 B:1
• Conservation: PhyloP100: -0.0830
• Publications: 30 publications found

Genes affected

PROS1 (HGNC:9456): (protein S) This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]

PROS1 Gene-Disease associations (from GenCC):

• thrombophilia due to protein S deficiency, autosomal dominant

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• thrombophilia due to protein S deficiency, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a domain Laminin G-like 2 (size 182) in uniprot entity PROS_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_000313.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.58456 (below the threshold of 3.09). Trascript score misZ: 1.9528 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein S deficiency, autosomal dominant, thrombophilia due to protein S deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein S deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009359419).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00242 (369/152304) while in subpopulation NFE AF = 0.00397 (270/68030). AF 95% confidence interval is 0.00358. There are 0 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000313.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	NM_000313.4	MANE Select	c.1501T>C	p.Ser501Pro	missense	Exon 13 of 15	NP_000304.2
	PROS1	NM_001314077.2		c.1597T>C	p.Ser533Pro	missense	Exon 14 of 16	NP_001301006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROS1	ENST00000394236.9	TSL:1 MANE Select	c.1501T>C	p.Ser501Pro	missense	Exon 13 of 15	ENSP00000377783.3
	PROS1	ENST00000407433.6	TSL:1	c.1456T>C	p.Ser486Pro	missense	Exon 13 of 15	ENSP00000385794.2
	PROS1	ENST00000650591.1		c.1597T>C	p.Ser533Pro	missense	Exon 14 of 16	ENSP00000497376.1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 369 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00202 AC: 509 AN: 251434 AF XY: 0.00218

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00317 AC: 4631 AN: 1461642 Hom.: 8 Cov.: 31 AF XY: 0.00313 AC XY: 2274 AN XY: 727128

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00179 AC: 80 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86250

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00378 AC: 4207 AN: 1111800

Other (OTH) AF: 0.00277 AC: 167 AN: 60388

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74484

African (AFR) AF: 0.000457 AC: 19 AN: 41558

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00397 AC: 270 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00285 Hom.: 0

Bravo AF: 0.00254

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Thrombophilia due to protein S deficiency, autosomal dominant Pathogenic:1 Uncertain:3

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 16, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

not provided Pathogenic:1 Uncertain:2

Oct 15, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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)

Sep 18, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PS3, PS4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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.

not specified Uncertain:1 Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Protein S Heerlen Pathogenic:1

Jun 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Optic atrophy Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thrombophilia due to protein S deficiency, autosomal recessive Uncertain:1

Oct 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Hereditary thrombophilia due to congenital protein S deficiency Uncertain:1

Sep 15, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	6.5
DANN	Benign	0.83
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.083
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.37
Sift	Benign	0.13	T
Sift4G	Benign	0.099	T
Polyphen		0.84	P
Vest4		0.35
MVP		0.79
MPC		0.29
ClinPred		0.0041	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.58
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918472; hg19: chr3-93598150;