NM_000407.5:c.315del

CA322079952

Gene: GP1BB

Condition: Bernard-Soulier syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 3d0a28c5-ecb7-4689-9f7d-6ceba4504b27

Approved on: 2025-02-11

Published on: 2025-02-14

HGVS expressions

NM_000407.5:c.315del
NC_000022.11:g.19724158del
CM000684.2:g.19724158del
NC_000022.10:g.19711681del
CM000684.1:g.19711681del
NC_000022.9:g.18091681del
NG_007974.1:g.5616del
ENST00000366425.4:c.315del
ENST00000366425.3:c.315del
ENST00000431044.5:c.*1400del
ENST00000455843.5:c.*1400del
ENST00000470814.1:n.2287del
NM_000407.4:c.315del
NR_037611.1:n.4055del
NR_037612.1:n.2559del

Pathogenic

• Met criteria codes: PM3 PVS1_Strong PM2_Supporting PP4_Moderate PS3_Supporting

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BB Version 1.0.0

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000407.5:c.315del (p.Gly106AlafsTer87) variant in exon 2 of the GP1BB gene is a frameshift variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove 7% of the protein, including the critical transmembrane domain (PVS1_Strong). At least one patient (Proband 1 in PMID:10216092) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry with less than 10% expression of GP9, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Direct sequence analysis of the entire coding region of PCR-amplified GPIba, GPIbb, GPIX, and GPV was performed as well as FISH for deletion analysis, for the patient (PP4_Moderate). This variant has been detected in at least 1 proband with Bernard-Soulier syndrome. This individual was compound heterozygous for this variant and the 22q11.2 deletion including GP1BB (PMID: 10216092; PM3). Surface expression of GP1b and GP9 was measured by flow cytometry in 293T cells transiently co-transfected with the c.315del (p.Gly106AlafsTer87) variant GP1bb and wild type GP1ba and GP9, with no detectable GPIX on the cell surface, indicating that this variant impacts protein function (PMID: 10216092)(PS3_supporting). This variant is absent from gnomAD v4.1 (PM2_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: PVS1_Strong, PP4_Moderate, PM2_supporting, PM3 and PS3_Supporting (VCEP specifications version 1).

Met criteria codes

• PM3: This variant has been detected in at least 1 probands with Bernard-Soulier syndrome. This individual was compound heterozygous for this variant and the 22q11.2 deletion which included GP1BB. (PMID: 10216092, PM3 points= 1 point).
• PVS1_Strong: The NM_000407.5:c.315del (p.Gly106AlafsTer87) variant in exon 2 of the GP1BB gene 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 (7%), including the critical transmembrane domain (PVS1_Strong).
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• PP4_Moderate: At least one patient (Proband 1 in PMID:10216092) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry with less than 10% expression of GP9, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Direct sequence analysis of the entire coding region of PCR-amplified GPIba, GPIbb, GPIX, and GPV was performed as well as FISH for deletion analysis, for the patient (PP4_Moderate).
• PS3_Supporting: Surface expression of GP1b and GP9 was measured by flow cytometry in 293T cells transiently co-transfected with the c.315del (p.Gly106AlafsTer87) variant GP1b and wild type GP1a and GP9, in the presence of the mutant GPIbb, GPIX is not detectable on the cell surface, indicating that this variant impacts protein function (PMID: 10216092)(PS3_supporting).