Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000407.5(GP1BB):c.127G>T (p.Gly43Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10102316

812970 (ClinVar)

Gene: GP1BB

Condition: Bernard-Soulier syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 075a94c8-c17a-4fbe-afe7-8e8e859123f7

Approved on: 2025-02-11

Published on: 2025-02-17

HGVS expressions

NM_000407.5:c.127G>T

NM_000407.5(GP1BB):c.127G>T (p.Gly43Trp)

NC_000022.11:g.19723970G>T

CM000684.2:g.19723970G>T

NC_000022.10:g.19711493G>T

CM000684.1:g.19711493G>T

NC_000022.9:g.18091493G>T

NG_007974.1:g.5428G>T

ENST00000366425.4:c.127G>T

ENST00000366425.3:c.127G>T

ENST00000431044.5:c.*1212G>T

ENST00000455843.5:c.*1212G>T

ENST00000470814.1:n.2099G>T

NM_000407.4:c.127G>T

NR_037611.1:n.3867G>T

NR_037612.1:n.2371G>T

Uncertain Significance

PP3_Moderate PM3_Supporting

PS4 PP4 PM2 BS1

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BB Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.127G>T variant in GP1BB is a missense variant predicted to cause substitution of Glycine by Tryptophan at amino acid 43 (p.Gly43Trp). The computational predictor REVEL gives a score of 0.887, which is above the ClinGen PD VCEP threshold of >0.773 and predicts a damaging effect on function (PP3_Moderate). Patient BSS64 (PMID: 24934643) is reported homozygous (PM3_supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3_Moderate, PM2_supporting.

PP3_Moderate

The computational predictor REVEL gives a score of 0.887, which is above the ClinGen PD VCEP threshold of >0.773 and predicts a damaging effect on function (PP3_Moderate).

PM3_Supporting

BSS64 (PMID: 24934643) is reported homozygous (PM3_supporting).

PS4

PMID: 28064200 reports two heterozygous individuals with macrothrombocytopenia -- C-2 is reported with macrothrombocytopenia (120x10^9 platelets/l; MPV not provided); J-8 macrothrombocytopenia (125x10^9/l; 13.5fl MPV) 0.25pt total 0.25pt is insufficient for PS4_supporting

PP4

This variant has been reported in the literature and on ClinVar with autosomal dominant macrothrombocytopenia (PMIDs: 32581362, 28064200) but not with Bernard-Soulier Syndrome (BSS). One patient from internal data had a historical diagnosis of BSS with a history of heavy menstrual bleeding, easy bruising, and macrothrombocytopenia. However, there was normal platelet aggregation and ATP release, inconsistent with BSS. Additionally, there was normal platelet glycoprotein testing with GPIIb of 143%, GPIIIa of 134%, GPIX of 80% and GPIb-alpha of 110%.

PM2

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00006612 (based on 2/5368 alleles) in the Middle Eastern population above the <0.0000651678 threshold for PM2_Supporting but below >0.0005 for BS1.

BS1

Curation History

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