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]

Link to SEPIO compliant JSON-LD document

CA8622982

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 326c5d01-3a6b-409b-8833-9ac2f0b93f0a

HGVS expressions

NM_000212.3:c.567del

NC_000017.11:g.47284648del

CM000679.2:g.47284648del

NC_000017.10:g.45362014del

CM000679.1:g.45362014del

NC_000017.9:g.42717013del

NG_008332.2:g.35807del

ENST00000559488.7:c.567del

ENST00000559488.5:c.567del

ENST00000560629.1:n.532del

ENST00000571680.1:c.567del

NM_000212.2:c.567del

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM2_Supporting

PM3 PP4

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 Version 2.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.3(ITGB3):c.567del (p.Tyr190ThrfsTer17) found in a compound heterozygous proband (PMID:28748566) causes a premature stop codon at exon 5 and is predicted to undergo nonsense mediated decay (PVS1). The mutation was not found in gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1 and PM2_supporting.

PVS1

The c.567del (p.Tyr190ThrfsTer17) variant in exon 4 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 5/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PM2_Supporting

The highest population minor allele frequency in gnomAD v[2.1.1] is [0.000008793] (1/113728 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).

PM3

This variant has been detected in at least 1 proband with Glanzmann Thrombasthenia. For 1 of those individuals, 1 was compound heterozygous for this variant and a pathogenic variant not specified in trans (NM_000212.3(ITGB3):c.1525C>T (p.Gln509Ter), (PMID:28748566, CAID:CA400029664). Not considered here to avoid circularity.

PP4

At least one patient (Patient 21 in PMID:28748566) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists. Additionally, αIIbβ3 surface expression was reduced to <5% (<25%), as measured by Flow Cytometry. However, a normal response to ristocetin, which is characteristic of GT was not reported (Not Met).

Approved on: 2022-11-15

Published on: 2022-12-07

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