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_000419.5:c.48G>A

CA399807046

1879030 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 4f031968-cbb7-4531-ae38-579af7ff6b20

Approved on: 2025-05-01

Published on: 2025-05-02

HGVS expressions

NM_000419.5:c.48G>A

NC_000017.11:g.44389426C>T

CM000679.2:g.44389426C>T

NC_000017.10:g.42466794C>T

CM000679.1:g.42466794C>T

NC_000017.9:g.39822320C>T

NG_008331.1:g.5080G>A

ENST00000262407.6:c.48G>A

ENST00000262407.5:c.48G>A

NM_000419.3:c.48G>A

NM_000419.4:c.48G>A

Likely Pathogenic

PM3_Supporting PVS1_Moderate PM2_Supporting PP4_Moderate

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.48G>A (p.Trp16Ter) variant in exon 1 is a nonsense variant in biologically-relevant-exon 1/30. Premature termination codons within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_Moderate. At least one patient (UPN 1 in PMID: 16879215) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 5.6%, as measured by flow cytometry. UPN 1 is homozygous for this variant (PM3_supporting; PMID: 16879215). This variant is absent from gnomAD v4.1 (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_moderate, PM2_supporting, PM3_supporting, PP4_moderate.

PM3_Supporting

UPN 1 is homozygous for this variant (PM3_supporting; PMID: 16879215).

PVS1_Moderate

The NM_000419.5(ITGA2B):c.48G>A (p.Trp16Ter) variant in exon 1 is a nonsense variant in biologically-relevant-exon 1/30. Premature termination codon within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_moderate.

PM2_Supporting

This variant is absent from gnomAD v4.1 (PM2_Supporting).

PP4_Moderate

At least one patient (UPN 1 in PMID: 16879215) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 5.6%, as measured by flow cytometry. However, ITGA2B and ITGB3 were not sequenced across all exons and intron/exon boundaries.

Curation History

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