17-4932706-CA-C

Position:

• chr17-4932706-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4 PM2_Supporting PVS1_Strong PS3_Supporting PM3

This summary comes from the ClinGen Evidence Repository: The c.104del (p.Lys35ArgfsTer4) variant in GP1BA is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). At least one patient (Patient GA in PMID:8950770) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). They also had thrombocytopenia, giant platelets, and life-long severe bleeding, including recurrent bruising and prolonged bleeding time. This variant has been detected in at least 2 probands with Bernard-Soulier syndrome (PMID:8950770 and 36507135). These individuals were both homozygous for the variant (PM3). Surface expression of GP1A measured by flow cytometry in mouse L cells transiently co-transfected with c.104del (p.Lys35ArgfsTer4) variant GP1A and wild type GP1B-GP9 showed undetectable expression at 0% WT levels, indicating that this variant impacts protein function (PMID:8950770, PS3_supporting). The Grpmax Filtering allele frequency in gnomAD v4.1.0 is 3.000e-7 (based on 2/1179868 alleles) in the European non Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001114; PM2_Supporting). 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: PVS1_Strong, PP4, PM2_Supporting, PM3, and PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658798681/MONDO:0009276/079

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GP1BA NM_000173.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.00100

Genes affected

GP1BA (HGNC:4439): (glycoprotein Ib platelet subunit alpha) Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.104delA	p.Lys35fs	frameshift_variant	2/2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6	c.104delA	p.Lys35fs	frameshift_variant	2/2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+1635delT		intron_variant				ENSP00000496907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461698 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2020

This sequence change results in a premature translational stop signal in the GP1BA gene (p.Lys35Argfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 618 amino acids of the GP1BA protein. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GP1BA protein. Other variant(s) that disrupt this region (p.Trp540*) have been determined to be pathogenic (PMID: 9233564, 9639514). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been reported to affect GP1BA protein function (PMID: 8950770). This variant has been observed in an individual affected with Bernard-Soulier syndrome (PMID: 8950770). This variant is also known as Lys19Argfs in the literature. ClinVar contains an entry for this variant (Variation ID: 523620). -

Bernard Soulier syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Aug 14, 2017

This heterozygous variant in the GP1BA gene was found in a patient with suspicion of Bernard Soulier syndrome, which can be transmitted in an autosomal recessive or dominant manner. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555549041; hg19: chr17-4836001;