GP1BB p.Pro90Ser

NM_000407.5(GP1BB):c.268C>T is a missense variant (p.Pro90Ser), which has been reported in one homozygous proband with Bernard-Soulier syndrome. At least one patient (Patient BSS-8 in PMID:25539746) with this variant had aggregation absent for ristocetin and present for all other agonists, and flow cytometry revealed that the GPIbα and GPIX expression was severely reduced (<10% compared to controls), which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes is specific to GP1bb (PP4_moderate). Additionally, the patient had macrothrombocytopenia and excessive mucocutaneous bleeding which is consistent with Bernard-Soulier syndrome. The Grpmax filtering allele frequency in gnomaDv4.1 is 0.000004490 (based on 2/74000 alleles) in the South Asian population, which is below the <0.0000651678 threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.771, which is above the ClinGen PD VCEP PP3 threshold of >0.644 and predicts a damaging effect on GP1BB function (PP3). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome c.269C>G (p.Pro90Arg) (PMID:21699652), it is classified Likely Pathogenic by the PD-VCEP (PM5_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: PP3, PP4_moderate, PM2_supporting, PM5_supporting, and PM3_supporting (VCEP specifications version 1).