chr3-129061921-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_StrongPM3PS3_SupportingPP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The c.182A>G (p.Asn61Ser) variant in GP9 is known for being frequently reported in BSS patients of European ancestry. It has been detected in at least 30 probands with Bernard-Soulier syndrome. At least 16 probands included in this curation have origin in Central or Northern Europe (France, Finland, Sweden, Germany, Belgium, Austria, and England). The literature supports the hypothesis of Koskela et al., which suggests that the c.182A>G (p.Asn61Ser) variant is an ancient founder mutation in this region (PMID:10227459). At least one patient with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes (PP4_moderate, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. At least 2 of the probands included in this curation were homozygous for the variant and were confirmed to have the variants in trans (PM3; PMIDs: 8049428, 14510954, 8856096, 10227459, 11297032). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus 3 (>2) affected family members, all with the homozygous genotype. (PP1_strong; PMID:19404517). The Grp max filtering allele frequency in gnomAD v4.1 is 0.0008047 (1001/1179870 alleles) in the European (Non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0007 for GP9), and therefore meets this criterion (BS1), however since this is a known founder variant BS1 will not be applied. The computational predictor REVEL gives a score of 0.721, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). A zebrafish model made by deleting 17bps in exon 2 of gp9 using CRISPR-Cas9 demonstrated thrombocytopenia and abnormal bleeding. The thrombocytopenia phenotype in the zebrafish was rescued using a wild-type copy of human GP9. The human copy of GP9 containing the c.182A>G variant failed to rescue the same phenotype, indicating that this variant impacts protein function (PMID:34407604)(PS3_Supporting).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP3, PP4_moderate, PP1_Strong, PS3_Supporting. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA123173/MONDO:0009276/083

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

GP9
NM_000174.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 3.62

Publications

19 publications found

Variant links:

Genes affected

GP9 (HGNC:4444): (glycoprotein IX platelet) This gene encodes a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib, a platelet surface membrane glycoprotein complex that functions as a receptor for von Willebrand factor. The complete receptor complex includes noncovalent association of the alpha and beta subunits with the protein encoded by this gene and platelet glycoprotein V. Defects in this gene are a cause of Bernard-Soulier syndrome, also known as giant platelet disease. These patients have unusually large platelets and have a clinical bleeding tendency. [provided by RefSeq, Oct 2008]

GP9 Gene-Disease associations (from GenCC):

Bernard-Soulier syndrome
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

GP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP9	NM_000174.5 link	c.182A>G	p.Asn61Ser	missense_variant	Exon 3 of 3	ENST00000307395.5	NP_000165.1	P14770
GP9	XM_047447997.1 link	c.182A>G	p.Asn61Ser	missense_variant	Exon 2 of 2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5 link	c.182A>G	p.Asn61Ser	missense_variant	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4		P14770

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000479

AC:

119

AN:

248302

AF XY:

0.000498

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.000936

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000701

AC:

1025

AN:

1461474

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

470

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33472

American (AMR)

AF:

0.0000895

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000864

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000835

AC:

928

AN:

1111866

Other (OTH)

AF:

0.000696

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000697

AC:

106

AN:

152164

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68004

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000876

Hom.:

Bravo

AF:

0.000627

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Bernard Soulier syndrome

Pathogenic:9Other:1

Feb 21, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Aug 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GP9 c.182A>G (p.Asn61Ser) missense variant has been reported in four studies in which it is found in a total of ten individuals with bleeding abnormalities characteristic of Bernard-Soulier syndrome, including in six in a homozygous state and in four (including three siblings) in a compound heterozygous state (Wright et al. 1993; Clemetson et al. 1994; Sachs et al. 2003; Bragadottir et al. 2015). The variant was also found in a heterozygous state in six unaffected family members. The p.Asn61Ser variant was absent from 208 control alleles and is reported at a frequency of 0.001073 in the non-Finnish European population of the Exome Aggregation Consortium. Based on the evidence, the p.Asn61Ser variant is classified as pathogenic for Bernard-Soulier syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Aug 13, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

May 18, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.182A>G (p.Asn61Ser) variant in GP9 is known for being frequently reported in BSS patients of European ancestry. It has been detected in at least 30 probands with Bernard-Soulier syndrome. At least 16 probands included in this curation have origin in Central or Northern Europe (France, Finland, Sweden, Germany, Belgium, Austria, and England). The literature supports the hypothesis of Koskela et al., which suggests that the c.182A>G (p.Asn61Ser) variant is an ancient founder mutation in this region (PMID:10227459). At least one patient with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes (PP4_moderate, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. At least 2 of the probands included in this curation were homozygous for the variant and were confirmed to have the variants in trans (PM3; PMIDs: 8049428, 14510954, 8856096, 10227459, 11297032). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus 3 (>2) affected family members, all with the homozygous genotype. (PP1_strong; PMID:19404517). The Grp max filtering allele frequency in gnomAD v4.1 is 0.0008047 (1001/1179870 alleles) in the European (Non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0007 for GP9), and therefore meets this criterion (BS1), however since this is a known founder variant BS1 will not be applied. The computational predictor REVEL gives a score of 0.721, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). A zebrafish model made by deleting 17bps in exon 2 of gp9 using CRISPR-Cas9 demonstrated thrombocytopenia and abnormal bleeding. The thrombocytopenia phenotype in the zebrafish was rescued using a wild-type copy of human GP9. The human copy of GP9 containing the c.182A>G variant failed to rescue the same phenotype, indicating that this variant impacts protein function (PMID:34407604)(PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP3, PP4_moderate, PP1_Strong, PS3_Supporting. (VCEP specifications version 1) -

Mar 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GP9 c.182A>G (p.Asn61Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 248302 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GP9 causing Bernard Soulier Syndrome (0.00048 vs 0.00074), allowing no conclusion about variant significance. c.182A>G has been reported in the literature in multiple individuals affected with Bernard Soulier Syndrome (e.g. Sachs_2003). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 14510954). ClinVar contains an entry for this variant (Variation ID: 13529). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PP5, PM3_strong, PS4_moderate -

Aug 11, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25370924, 14510954, 8049428, 31064749, 8481514, 27934591, 28131619, 28765788, 28960434, 30431218, 31980526, 32581362, 31589614, 33553065, 24934643) -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 61 of the GP9 protein (p.Asn61Ser). This variant is present in population databases (rs5030764, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 8481514, 14510954, 25370924, 28131619, 28765788). It has also been observed to segregate with disease in related individuals. This variant is also known as Asn45Ser. ClinVar contains an entry for this variant (Variation ID: 13529). 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. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GP9: PM3:Very Strong, PP1:Moderate, PM2:Supporting -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macrothrombocytopenia

Pathogenic:2

Mar 22, 2019

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Bernard-Soulier syndrome type C

Pathogenic:1

Oct 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GP9-related disorder

Pathogenic:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GP9 c.182A>G variant is predicted to result in the amino acid substitution p.Asn61Ser. This variant, also described as p.Asn45Ser in the literature, has been reported in the homozygous or compound heterozygous states in multiple individuals with Bernard-Soulier syndrome (Wright et al. 1993. PubMed ID: 8481514; Clemetson et al. 1994. PubMed ID: 8049428; Liang et al. 2005. PubMed ID: 16268478; Romasko et al. 2018. PubMed ID: 28960434; Saes et al. 2019. PubMed ID: 30431218). This variant is reported in 0.095% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Thrombocytopenia

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.53

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

PhyloP100

3.6

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.94

MPC

0.62

ClinPred

0.15

GERP RS

4.2

Varity_R

0.79

gMVP

0.92

Mutation Taster

=61/39

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over