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.2159T>C

CA399798955

996189 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 7e3fd2f9-4fdf-4e5f-90ee-eb4dec2d2fef

Approved on: 2024-03-07

Published on: 2024-03-08

HGVS expressions

NM_000419.5:c.2159T>C

NC_000017.11:g.44377726A>G

CM000679.2:g.44377726A>G

NC_000017.10:g.42455094A>G

CM000679.1:g.42455094A>G

NC_000017.9:g.39810620A>G

NG_008331.1:g.16780T>C

ENST00000262407.6:c.2159T>C

ENST00000648408.1:c.1590T>C

ENST00000262407.5:c.2159T>C

ENST00000592462.5:n.954T>C

NM_000419.3:c.2159T>C

NM_000419.4:c.2159T>C

NM_000419.5(ITGA2B):c.2159T>C (p.Leu720Pro)

Uncertain Significance

PM2_Supporting PP4_Strong

PM3 BP4 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 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.2159T>C (p.Leu720Pro) missense variant has been reported in at least three compound heterozygous GT proband (PMID: 29675921, GT database 438, and doi.org/10.1182/blood.V110.11.3921.3921). GT5 of PMID: 29675921 meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. This variant is absent from all population cohorts in gnomADv4.0 (PM2_supporting) In summary this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM2_Supporting and PP4_strong.

PM2_Supporting

This variant is absent from all population cohorts in gnomADv4.0.

PP4_Strong

GT5 of PMID: 29675921 meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

PM3

Three compound heterozygous probands have been reported, which do not meet criteria for PM3. One with Pro23His (VUS without confirmation of phase), one with Ala777Asp (VUS without confirmation of phase), and one with Arg584Ter (Pathogenic but not meeting PM2).

BP4

The computational predictor REVEL gives a score of 0.672, which is above the ClinGen PD VCEP threshold of <0.25.

PP3

The REVEL score of 0.672 is below the threshold of >0.7 and there is no predicted impact on splicing.

Curation History

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