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.206C>T (p.Pro69Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA8314719

1285165 (ClinVar)

Gene: GP1BA

Condition: Bernard-Soulier syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 27d83667-1833-4c1b-9b16-69988d4ddacd

Approved on: 2025-02-11

Published on: 2025-02-12

HGVS expressions

NM_000173.7:c.206C>T

NM_000173.7(GP1BA):c.206C>T (p.Pro69Leu)

NC_000017.11:g.4932810C>T

CM000679.2:g.4932810C>T

NC_000017.10:g.4836105C>T

CM000679.1:g.4836105C>T

NC_000017.9:g.4776885C>T

NG_008767.2:g.5516C>T

ENST00000329125.6:c.206C>T

ENST00000649830.1:c.-888+1532G>A

ENST00000329125.5:c.206C>T

ENST00000611961.1:c.206C>T

NM_000173.6:c.206C>T

Benign

BA1

BS2 BP4 BP5 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.206C>T (p.Pro69Leu) occurs at a Grpmax filtering allele frequency in gnomAD v4.1 of 0.002916 (based on 3539/1179884 alleles) in the European (non-Finnish) population, (>0.001; BA1). This variant has been reported in at least two families with macrothrombocytopenia or Bernard-Soulier syndrome (PMIDs: 18065693, 25370924) but alternate causes of disease were identified. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 (ClinGen Platelet Disorders VCEP specifications version 1).

BA1

The Grpmax filtering allele frequency in gnomAD v4.1 is 0.002916 (based on 3539/1179884 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1).

BS2

The parent of DK I propositi (compound heterozygous for Met68fs and Tyr534fs, does not harbor Pro69Leu) is compound heterozygous for Met68fs and Pro69Leu and was not diagnosed with BSS, however phenotypic information to confirm unaffected status was not provided (PMID: 25370924; BS2_NotMet).

BP4

The computational predictor REVEL gives a score of 0.03, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP1BA function. SpliceAI gives a score of 0.01 for gain of an acceptor site 20bp away (delta score >0; BP4_NotMet)

BP5

In a a 3-generation pedigree (PMID: 18065693) with 5 individuals affected with a dominantly inherited macrothrombocytopenia, all 5 carry the D723H mutation in the β3 integrin and this Pro69Leu variant. Three additional unaffected family members also carry Pro69Leu but all are heterozygous no homozygotes. The macrothrombocytopenia was considered to be due to the D723H mutation in the β3 integrin but BP5 is not used by this VCEP.

PP4

Patient 55 (PMID: 30349881), with suspected inherited thrombocytopenia, was analyzed using panel-based sequencing. It is unclear in the report if the patient is heterozygous or homozygous for the variant but they are not asserted to have BSS.

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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