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]

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Variant: NM_000419.5:c.*165T>C

CA915940530

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9e0e109f-4abd-4e40-8a84-4c96f95cf129

Approved on: 2022-06-02

Published on: 2022-06-12

HGVS expressions

NM_000419.5:c.*165T>C

NC_000017.11:g.44372199A>G

CM000679.2:g.44372199A>G

NC_000017.10:g.42449567A>G

CM000679.1:g.42449567A>G

NC_000017.9:g.39805093A>G

NG_008331.1:g.22307T>C

ENST00000262407.6:c.*165T>C

ENST00000648408.1:n.2599T>C

ENST00000262407.5:c.*165T>C

ENST00000587295.5:n.478T>C

ENST00000588098.1:n.262T>C

NM_000419.3:c.*165T>C

NM_000419.4:c.*165T>C

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

PM3_Supporting PM2_Supporting PP4_Strong

BP7

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.*165T>C 3'UTR variant was identified homozygous (PM3_supporting) in at least one patient (GT75 in PMID: 25728920) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v3.1.2 (PM2_Supporting). ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1). These criteria reach Likely Pathogenic however, to our knowledge, there is no known disease mechanism for 3'UTR variants in Glanzmann thrombasthenia. In the absence of additional cases or functional data the ClinGen PD VCEP classifies this variant as uncertain significance for autosomal recessive Glanzmann Thrombasthenia.

PM3_Supporting

GT75 is homozygous for the c.*165T>C variant (PMID: 25728920; PM3_supporting)

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).

PP4_Strong

At least one patient (GT75in PMID: 25728920) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong)

BP7

This 3'UTR variant is not predicted to alter splicing but it is highly conserved with a phyloP score of 4.02898.

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