3-129061809-T-C

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

11
4
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

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]

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
GP9NM_000174.5 linkc.70T>C p.Cys24Arg missense_variant Exon 3 of 3 ENST00000307395.5 NP_000165.1 P14770
GP9XM_047447997.1 linkc.70T>C p.Cys24Arg missense_variant Exon 2 of 2 XP_047303953.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GP9ENST00000307395.5 linkc.70T>C p.Cys24Arg missense_variant Exon 3 of 3 1 NM_000174.5 ENSP00000303942.4 P14770

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
33
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:
19
AN:
243690
Hom.:
0
AF XY:
0.000106
AC XY:
14
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:
65
AN:
1460698
Hom.:
2
Cov.:
32
AF XY:
0.0000606
AC XY:
44
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:
1
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
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.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000495
AC:
6

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
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. -

Oct 14, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Bernard Soulier syndrome Pathogenic:3
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. -

-
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

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
D
BayesDel_noAF
Pathogenic
0.45
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.92
D
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.010
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.54
T
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-9.9
D
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.78
MVP
0.98
MPC
0.93
ClinPred
0.96
D
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.

Other links and lift over

dbSNP: rs28933378; hg19: chr3-128780652; API