Variant: NM_000173.7:c.785T>G

CA397318622

Gene: GP1BA

Condition: Bernard-Soulier syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 94b63243-02b8-48d8-bd3e-904e16b1f38b

Approved on: 2025-04-15

Published on: 2025-05-13

HGVS expressions

NM_000173.7:c.785T>G
NC_000017.11:g.4933389T>G
CM000679.2:g.4933389T>G
NC_000017.10:g.4836684T>G
CM000679.1:g.4836684T>G
NC_000017.9:g.4777464T>G
NG_008767.2:g.6095T>G
ENST00000329125.6:c.785T>G
ENST00000649830.1:c.-888+953A>C
ENST00000329125.5:c.785T>G
ENST00000611961.1:c.785T>G
NM_000173.6:c.785T>G

Uncertain Significance

• Met criteria codes: PM3_Supporting PP1 PP4 PM2_Supporting

• Not Met criteria codes: PP3

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 c.785T>G variant in GP1BA is a missense variant predicted to cause substitution of Valine by Glycine at amino acid 262 (p.Val262Gly). At least one patient (Patient BSS19.01 in PMID:23995613) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba 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 (PP4). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting). Additionally, the variant has been reported to segregate in this proband plus 1 additional homozygous BSS affected family member who displays significantly reduced surface expression of GP1BA and giant platelets). 1 pt total (PP1_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4, PM3_Supporting, PP1 and PM2_Supporting (VCEP specifications version 1).

Met criteria codes

• PM3_Supporting: This variant has been detected in at least 1 proband with Bernard-Soulier syndrome (PMID: 23995613). This individual was homozygous for the variant (0.5 PM3 points, PM3_Supporting).
• PP1: The variant has been reported to segregate in the proband plus 1 additional homozygous BSS affected family member who displays significantly reduced surface expression of GP1BA and giant platelets). 1 pt total (PP1_Supporting).
• PP4: At least one patient (Patient BSS19.01 in PMID:23995613) with this variant had aggregation absent for ristocetin and present for all other agonists and less than 10% expression of GPIba 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 (PP4).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.384, which is below the ClinGen PD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on GP1BA function. And the computational splicing predictor SpliceAI indicated that the variant has no predicted impact on splicing (Splice AI score <0.5).