The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: ITGA2B vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000419.5:c.1563T>A

CA290950094

1879034 (ClinVar)

Gene: ITGA2B
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: 72a0081f-a505-45f9-8aa9-3e831b6ec129
Approved on: 2025-04-15
Published on: 2025-05-13

HGVS expressions

NM_000419.5:c.1563T>A
NC_000017.11:g.44380283A>T
CM000679.2:g.44380283A>T
NC_000017.10:g.42457651A>T
CM000679.1:g.42457651A>T
NC_000017.9:g.39813177A>T
NG_008331.1:g.14223T>A
ENST00000262407.6:c.1563T>A
ENST00000648408.1:c.994T>A
ENST00000262407.5:c.1563T>A
ENST00000592226.5:n.1036T>A
ENST00000592462.5:n.358T>A
NM_000419.3:c.1563T>A
NM_000419.4:c.1563T>A
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Likely Pathogenic

Met criteria codes 2
PM2_Supporting PVS1
Not Met criteria codes 2
PP4 PM3

Evidence Links 0

Expert Panel

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.1563T>A (p.Cys521Ter) nonsense variant in exon 16/30 is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been observed in heterozygosity in an individual with a laboratory phenotype (platelet aggregation and surface expression) consistent with Glanzmann's thrombasthenia (GT), however a second ITGA2B variant was not identified and sufficient bleeding phenotype information to confirm if the individual's phenotype is specific for GT was not provided. This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary this variant meets 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, PM2_supporting. (VCEP specifications version 2.1)
Met criteria codes
PM2_Supporting
Variant not observed in gnomAD v4.1
PVS1
This variant introduces a termination codon at amino acid position 521 in exon 16/30. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function.
Not Met criteria codes
PP4
This variant was reported in heterozygosity in one individual (originally reported as CabGT-7 in PMID: 20020534, additional information reported as 306 — Patient 7 in Glanzmann's Thrombasthenia Database) with a platelet aggregation and surface expression laboratory phenotype consistent with Glanzmann's Thrombasthenia (abnormal response to multiple agonists and normal response to ristocetin; flow cytometry demonstrated reduced GPIIb and GPIIIa surface expression). However, sufficient bleeding phenotype information to meet PP4 was not provided.
PM3
This variant was reported in heterozygosity in one individual (CabGT-7, PMID: 20020534), however a second ITGA2B variant was not identified.
Curation History
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