Variant: NM_000173.7(GP1BA):c.434T>C (p.Leu145Pro)

Version: 1.0
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CA8314774

1684365 (ClinVar)

Gene: GP1BA (HGNC:2811)

Condition: Bernard-Soulier syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 9f80c092-c2c7-40c2-9f9e-f5b43af9c95b

Approved on: 2025-02-11

Published on: 2025-02-13

HGVS expressions

NM_000173.7:c.434T>C
NM_000173.7(GP1BA):c.434T>C (p.Leu145Pro)
NC_000017.11:g.4933038T>C
CM000679.2:g.4933038T>C
NC_000017.10:g.4836333T>C
CM000679.1:g.4836333T>C
NC_000017.9:g.4777113T>C
NG_008767.2:g.5744T>C
ENST00000329125.6:c.434T>C
ENST00000649830.1:c.-888+1304A>G
ENST00000329125.5:c.434T>C
ENST00000611961.1:c.434T>C
NM_000173.6:c.434T>C

Likely Pathogenic

• Met criteria codes: PP3_Moderate PM3 PS3_Supporting PP1 PP4

• Not Met criteria codes: PM2 BS1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BA Version 1.0.0

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000173.7(GP1BA):c.434T>C (p.Leu145Pro) missense variant occurs in the first amino acid of the fifth leucine-rich repeat of the GPIbα polypeptide and the computational predictor REVEL gives a score of 0.862, which is above the ClinGen PD VCEP threshold of >0.773 to predict a damaging effect on function (PP3_Moderate). At least three BSS patients have been reported with this variant, including 2 homozygotes (PMID: 10996832 and PMID: 7579348; PM3) and one compound heterozygote (PMID: 10089893) in trans with c.1601_1602del. At least one patient (Patient 1 in PMID: 7579348) 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 excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Patient 1 and their affected cousin are both homozygous for the variant (PMID: 7579348; PP1). Functional analysis was performed with both wild-type and mutant GPIbα cDNAs transiently transfected into L cells that had been previously transformed with stable constructs expressing GPIbβ and IX. Measured by flow cytometry, 43% of cells expressed GPIbα protein on their surface when transfected with normal GPIbα cDNA under the described conditions. However, no GPIbα expression could be appreciated on the surface of the cells transfected with the mutant GPIbα cDNA (PMID: 7579348; PS3_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: PM3, PP1, PP3_Moderate, and PP4.

Met criteria codes

• PP3_Moderate: The computational predictor REVEL gives a score of 0.862, which is above the ClinGen PD VCEP threshold of >0.773 and predicts a damaging effect on function (PP3_Moderate).
• PM3: At least three BSS patients have been reported with this variant, including 2 homozygotes (1pt; PMID: 10996832 and PMID: 7579348) and one compound heterozygote (PMID: 10089893) in trans with c.1601_1602del (does not affect this classification and not yet curated by the PD VCEP). Total 1pt (PM3)
• PS3_Supporting: Both wild-type and mutant GPIbα cDNAs were transiently transfected into L cells that had been previously transformed with stable constructs expressing GPIbβ and IX. Measured by flow cytometry, 43% of cells expressed GPIbα protein on their surface when transfected with normal GPIbα cDNA under the described conditions. However, no GPIbα expression could be appreciated on the surface of the cells transfected with the mutant GPIbα cDNA (PMID: 7579348; PS3_supporting)
• PP1: Both affected cousins are homozygous (PMID: 7579348; PP1)
• PP4: At least one patient (Patient 1 in PMID: 7579348) 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 excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome.

Not Met criteria codes

• PM2: The Grpmax filtering AF in gnomaDv4.1 is 0.00001746 (based on 4/74920 alleles) in the African/African American population, below the threshold of 0.0001114 for PM2_supporting. However, the highest population minor allele frequency in gnomAD v4.1 is 0.001031 (34/25018 alleles) in the Finnish population (not considered for the Grpmax FAF) which is higher than the ClinGen PD VCEP BA1 threshold (>0.001 for GP1BA) but bottlenecked populations are not considered for BA1. Given this conflicting information no population criteria are included.
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline