3-129061809-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_SupportingPP3PP1PP4PM3

This summary comes from the ClinGen Evidence Repository: The c.70T>C (p.Cys24Arg) variant in GP9 is a missense variant predicted to cause substitution of cystine by arginine at amino acid 24. This variant has been detected in at least 14 probands with Bernard-Soulier syndrome. All 14 of these individuals were homozygous for this variant at least 2 of those were confirmed in trans by parental testing (PMIDs:23402648, 21699652, 21173099, 11167791, 29119711; PM3). At least one patient (Patient BSS2.01 in PMID:23402648) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus one affected family member, both with the homozygous genotype with the p.Cys24Arg variant. (PP1; PMID:21173099). The computational predictor REVEL gives a score of 0.732, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). The human copy of this variant failed to rescue thrombocytopenia when expressed in mutant thrombocytopenic zebrafish embryos.In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP1, PP3, PP4, PS3_supporting. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA123181/MONDO:0009276/083

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 2 hom. )

Consequence

GP9
NM_000174.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 0.642

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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.70T>C	p.Cys24Arg	missense_variant	Exon 3 of 3	ENST00000307395.5	NP_000165.1	P14770
GP9	XM_047447997.1 link	c.70T>C	p.Cys24Arg	missense_variant	Exon 2 of 2		XP_047303953.1
GP9	XM_005247374.4 link	c.*272T>C		downstream_gene_variant			XP_005247431.2	P14770

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5 link	c.70T>C	p.Cys24Arg	missense_variant	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4		P14770

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000780

AC:

AN:

243690

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

132590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000593

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1460698

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000685

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000599

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Bernard Soulier syndrome

Pathogenic:4

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2020

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.70T>C (p.Cys24Arg) results in a non-conservative amino acid change located in the Leucine-rich repeat N-terminal domain (IPR000372) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 243690 control chromosomes. c.70T>C has been reported in the literature in multiple individuals (mostly homozygous) affected with Bernard Soulier Syndrome, and has been reported to be a common founder mutation (Sumitha_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 06, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.70T>C (p.Cys24Arg) variant in GP9 is a missense variant predicted to cause substitution of cystine by arginine at amino acid 24. This variant has been detected in at least 14 probands with Bernard-Soulier syndrome. All 14 of these individuals were homozygous for this variant at least 2 of those were confirmed in trans by parental testing (PMIDs:23402648, 21699652, 21173099, 11167791, 29119711; PM3). At least one patient (Patient BSS2.01 in PMID:23402648) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus one affected family member, both with the homozygous genotype with the p.Cys24Arg variant. (PP1; PMID:21173099). The computational predictor REVEL gives a score of 0.732, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). The human copy of this variant failed to rescue thrombocytopenia when expressed in mutant thrombocytopenic zebrafish embryos. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP1, PP3, PP4, PS3_supporting. (VCEP specifications version 1) -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:3

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 24 of the GP9 protein (p.Cys24Arg). This variant is present in population databases (rs28933378, gnomAD 0.06%). This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 11167791, 21173099, 21699652, 23402648). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys8Arg. ClinVar contains an entry for this variant (Variation ID: 13533). 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. This variant disrupts the p.Cys24 amino acid residue in GP9. Other variant(s) that disrupt this residue have been observed in individuals with GP9-related conditions (PMID: 21173099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Bernard-Soulier syndrome type C

Pathogenic:1

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.010

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-9.9

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.98

MPC

0.93

ClinPred

0.96

GERP RS

4.2

Varity_R

0.87

gMVP

0.98

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over