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(ITGA2B):c.1544+1G>A

Curation Version - 1.0
Curation History
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CA10575473

2895 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9b638038-9f07-4f3a-ab7b-ac3fede71eaf

Approved on: 2021-01-19

Published on: 2021-01-28

HGVS expressions

NM_000419.5:c.1544+1G>A

NM_000419.5(ITGA2B):c.1544+1G>A

NC_000017.11:g.44380385C>T

CM000679.2:g.44380385C>T

NC_000017.10:g.42457753C>T

CM000679.1:g.42457753C>T

NC_000017.9:g.39813279C>T

NG_008331.1:g.14121G>A

NM_000419.3:c.1544+1G>A

NM_000419.4:c.1544+1G>A

ENST00000262407.5:c.1544+1G>A

ENST00000592226.5:n.1017+1G>A

ENST00000592462.5:n.339+1G>A

Pathogenic

PVS1 PM3 PM2_Supporting PP4_Strong

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000419.5(ITGA2B):c.1544+1G>A is a canonical splice donor variant on intron 15 of ITGA2B, that was demonstrated to result in a frameshift leading to a premature stop codon due to abnormal splicing occuring in a cryptic splice site located 8 bp upstream from the mutation (PMIDs: 7620188, 21487445). This variant has been reported several times in French Manouche families with a GT phenotype. It has been reported to occur in a homozygous state in at least 16 individuals (PMIDs: 25728920, 22250950). It is absent from large population cohorts including gnomAD. This variant satisfies GT specific criteria for PVS1, PM3, PP4_Strong and PM2_Supporting and is therefore classified as Pathogenic for GT.

PVS1

This variant, c.1544+1G>A, is a canonical splice site variant that is predicted to cause disruption of the splice donor site on intron 15. This mutation was demonstrated to result in abnormal splicing occurring at an alternative donor site located 8 bp upstream from the mutation. This results in a frameshift leading to a premature stop codon in exon 17 of 30, predicted to lead to NMD. (PMIDs: 21487445, 7620188)

PM3

At least 16 GT patients, homozygous for the c.1544+1G>A variant have been reported in literature. (PMIDs: 222509500, 25728920) Maximum points possible for homozygous occurrence is 1 point; Therefore PM3 was applied.

PM2_Supporting

Absent from large population databases (gnomAD, 1000Genomes, ExAC).

PP4_Strong

Three probands with the c.1544+1G>A variant have been reported by PMID: 25728920. Of these, at least one proband met criteria for PP4_strong which included a history of significant mucocutaneous bleeding, absent platelet aggregation with three physiological agonists (but normal aggregation with ristocetin) and reduced (<5%) surface expression of αIIbβ3 demonstrated by flow cytometry. Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions (UTR). PMID: 25728920

Curation History

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