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_000173.7(GP1BA):c.92T>C (p.Val31Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA8314693

585094 (ClinVar)

Gene: GP1BA

Condition: Bernard-Soulier syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 143c642a-230a-4e13-8e33-dd5498edc2b7

Approved on: 2025-02-11

Published on: 2025-02-12

HGVS expressions

NM_000173.7:c.92T>C

NM_000173.7(GP1BA):c.92T>C (p.Val31Ala)

NC_000017.11:g.4932696T>C

CM000679.2:g.4932696T>C

NC_000017.10:g.4835991T>C

CM000679.1:g.4835991T>C

NC_000017.9:g.4776771T>C

NG_008767.2:g.5402T>C

ENST00000329125.6:c.92T>C

ENST00000649830.1:c.-888+1646A>G

ENST00000329125.5:c.92T>C

ENST00000611961.1:c.92T>C

NM_000173.6:c.92T>C

Uncertain Significance

BS1

BS2 BP4 PM5 PP4 PP3

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 GP1BA Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The missense variant NM_000173.7(GP1BA):c.92T>C (p.Val31Ala) has been reported in one macrothrombocytopenia patient heterozygous for this variant (PMID: 34400424) however the same variant was detected in the mother with normal laboratory parameters. No BSS patients have been reported to our knowledge. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0006253 (based on 784/1179792 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0005; BS1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS1 (ClinGen Platelet Disorders VCEP specifications version 1).

BS1

The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0006253 (based on 784/1179792 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0005), and therefore meets this criterion (BS1). Of note, the highest MAF is in the Ashkenazi Jewish population at 0.01591 including 4 homozygote, but as a bottle-necked population it is not considered for BA1.

BS2

PMID: 34400424 Detected same heterozygous mutation in patient and her mother. Laboratory parameters and flow cytometry of mother did not support diagnosis of Bernard–Soulier syndrome but insufficient information is available for BS2.

BP4

The computational predictor REVEL gives a score of 0.452, which is above the ClinGen PD VCEP BP4 threshold of <0.290.

PM5

NM_000173.7:c.91G>T (p.Val31Leu) has been observed at the same amino acid residue, however it has only been reported with dominant isolated giant platelet disorder (PMID: 26849716) and has not been assessed as Pathogenic for BSS.

PP4

One patient has been reported heterozygous for this variant (PMID: 34400424). Although giant platelets and decreased ristocetin- induced platelet aggregation in the patient made the authors consider Bernard-Soulier syndrome, flow cytometry (CD41a 86.2%, CD42a 92.9%, CD42b 92.5%, and CD61 87.8%) and gene analysis did not support the diagnosis of Bernard- Soulier syndrome.

PP3

The computational predictor REVEL gives a score of 0.452, 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 (score 0.00).

Curation History

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