GP9 p.Leu7Pro

The c.20T>C variant in GP9 is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 7 (p.Leu7Pro). At least one patient (Patient 1 in PMID: 12100158) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba, GP1bb and GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Functional evidence meeting PS3_supporting is accepted in lieu of del/dup analysis, as it addresses concerns about misattribution of phenotypic effects to the variant due to an undetected CNV(PP4_Moderate). This individual was homozygous for the variant (0.5 points, PM3_Supporting). Surface expression of GP1a, GP1b, and GP9 measured by flow cytometry in CHO cells transiently co-transfected with c.20T>C (p.Leu7Pro) variant GP9 and wild type GP1a and GP1b showed absent expression, indicating that this variant impacts protein function (PMID: 12100158)(PS3_supporting). The computational predictor REVEL gives a score of 0.731, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on GP9 function (PP3). This variant is absent from gnomAD v4.1.0 (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: PP4_Moderate, PM3_Supporting, PS3_Supporting, PP3 and PM2_Supporting (VCEP specifications version 2; date of approval 09/04/2025).