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.985G>T

CA399804719

1030781 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: b2c81f25-21e7-45e9-a5e8-ee5e5513cbf4

Approved on: 2024-04-16

Published on: 2024-04-16

HGVS expressions

NM_000419.5:c.985G>T

NC_000017.11:g.44383907C>A

CM000679.2:g.44383907C>A

NC_000017.10:g.42461275C>A

CM000679.1:g.42461275C>A

NC_000017.9:g.39816801C>A

NG_008331.1:g.10599G>T

ENST00000262407.6:c.985G>T

ENST00000648408.1:c.416G>T

ENST00000262407.5:c.985G>T

ENST00000589645.5:n.436G>T

ENST00000591990.5:n.530G>T

ENST00000592226.5:n.225G>T

NM_000419.3:c.985G>T

NM_000419.4:c.985G>T

Likely Pathogenic

PM2_Supporting PP4_Moderate PM3_Strong

BP4 PS3 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 ITGA2B missense variant NM_000419.5:c.985G>T replaces the valine residue with a phenylalanine residue (p.Val329Phe) and is absent from control population databases. This variant has been observed in four individuals (in homozygosity in GT-56, PMID: 30792900 and https://doi.org/10.24911/IJMDC.51-1568613172; in compound heterozygosity in Patient M, PMID: 12424194 (in trans with ITGA2B variant c.1232dup (p.Tyr411Ter), provisionally classified as pathogenic by the Platelet Disorders VCEP) and in heterozygosity in GT-62, PMID: 30792900 (second ITGA2B variant not identified)) suspected to have Glanzmann's thrombasthenia (GT). At least one of these individuals was reported to have a bleeding and laboratory phenotype specific for GT (https://doi.org/10.24911/IJMDC.51-1568613172). Although functional studies of this variant have been reported (PMID: 12424194; flow cytometric detection of αIIbβ3 positive cells following transient transfection of ITGA2B cDNA carrying this variant, immunoprecipitation of αIIb in lysates of transiently transfected cells, and pulse-chase analysis), these experiments did not meet the requirements for PS3. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_strong, PP4_moderate.

PM2_Supporting

This variant is absent from gnomAD v4.0.0 (PM2_Supporting).

PP4_Moderate

All requirements for PP4_moderate are met (https://doi.org/10.24911/IJMDC.51-1568613172): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin.

PM3_Strong

This variant has been observed in one individual (Patient M, PMID: 12424194) in trans with ITGA2B variant c.1232dup (p.Tyr411Ter), classified as pathogenic by the Platelet Disorders VCEP (1pt) and in homozygosity in two individuals (GT-56, PMID: 30792900 and https://doi.org/10.24911/IJMDC.51-1568613172; 1pt). These occurrences are sufficient to apply PM3_strong (2pt). This variant was also identified in heterozygosity (GT-62, PMID: 30792900) with no second ITGA2B variant identified (although ITGB3 variant c.1265G>A (p.Ser422Asn) was also observed in this proband in heterozygosity).

BP4

See explanation for PP3.

PS3

PMID: 12424194: ITGA2B cDNA carrying the c.985G>T variant was transiently transfected into 293T cells. αIIbβ3 receptor expression on the cell surface was measured by flow cytometry and shown to be reduced to approximately 28% compared to wild type (13% ± 5% of cells were positive for the αIIbβ3 receptor compared to 46% ± 12% of cells transiently transfected with wild type cDNA). However, this evidence was not used to support PS3 at any level of strength because the level of αIIbβ3 cell surface expression was not measured, only whether cells were positive or negative for surface αIIbβ3. Other experiments reported in this publication (immunoprecipitation of αIIb in lysates from the transfected cells and pulse-chase analyses) also did not meet the requirements to apply PS3 at any level of strength.

PP3

The REVEL score for this variant is 0.469, below the VCEP-established threshold of ≥0.7 to apply PP3 and above the VCEP-established threshold of <0.25 to apply BP4. Additionally, splice predictors (SpliceAI and MaxEntScan) do not predict a damaging effect on splicing.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.