GP9 p.Phe71Ser

The c.212C>T variant in GP9 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 71. This variant has been detected in at least 16 probands with Bernard-Soulier syndrome. This variant has been detected in at least 8 probands with supporting laboratory results described in the literature (PM3_Strong). Two of these probands were compound heterozygous for this variant and another variant (c.266G>A [p.Cys89Tyr], c.182A>G [p.Asn61Ser]) (PMID:24934643). Six of these probands were homozygous for the variant, with at least 3 of these confirmed using parental testing or other methods (PMIDs: 9163595, 432024, 21173099, 21699652, 25539746). At least one patient (proband in PMID: 9432024) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry with less than 10% expression of GPIba, which is highly specific for Bernard-Soulier syndrome (PP4). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband plus two affected family members, all with the homozygous genotype (PP1_moderate; PMID:17763149). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome c.212T>G, p.Phe71Cys (PMID:21699652), classified likely pathogenic by the ClinGen PD VCEP (PM5_supporting). The highest minor allele frequency in gnomaDv4.1 is 0.00003294 (3/91084 alleles) in the South Asian genetic ancestry group, which is below the <0.0000329 threshold for PM2_supporting. Surface expression of GP1Ba measured by flow cytometry in CHO-K1 cells transiently co-transfected with the c.212T>C variant in GP9 and wild type GP1Bb showed decreased expression at ~17% (<25%) WT levels, indicating that this variant impacts protein function (PMID:10527407; PS3_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: PP4, PM3_strong, PM2_Supporting, PS3_Supporting, PP1_Moderate, PM5_supporting (VCEP specifications version 1).