Variant: NM_000212.3(ITGB3):c.614+1G>T

CA400023344

1210175 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: c49a54d1-519d-4936-ad13-a218a87cc99b

Approved on: 2024-09-05

Published on: 2024-09-30

HGVS expressions

NM_000212.3:c.614+1G>T
NM_000212.3(ITGB3):c.614+1G>T
NC_000017.11:g.47284696G>T
CM000679.2:g.47284696G>T
NC_000017.10:g.45362062G>T
CM000679.1:g.45362062G>T
NC_000017.9:g.42717061G>T
NG_008332.2:g.35855G>T
ENST00000696963.1:c.614+1G>T
ENST00000559488.7:c.614+1G>T
ENST00000559488.5:c.614+1G>T
ENST00000560629.1:c.579+1G>T
ENST00000571680.1:c.614+1G>T
NM_000212.2:c.614+1G>T

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PP1 PP4 PM3

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

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.614+1G>T variant on ITGB3 gene is a canonical splice donor variant that has been reported previously in the context of Glanzmann Thrombasthenia (PMID: 25728920). It is predicted to cause a disruption of the canonical donor splice site in intron 4, this is expected to cause a frameshift with premature stop at codon 122 (exon 5 of 15), therefore NMD would be expected. (PVS1). It is absent from all major population cohorts in gnomADv4.1 (PM2_supporting). This variant has been reported in homozygosity in two symptomatic siblings who meet diagnostic criteria for GT phenotype (PMID: 25728920). However, the siblings are homozygous for both c.614+1G>T and Arg228His and while this splice variant is Likely Pathogenic an impact of the missense variant can not be excluded so this case has not been considered in the classification of this variant. This variant meets GT-specific criteria for PVS1 and PM2_supporting and is therefore classified as Likely Pathogenic.

Met criteria codes

• PVS1: This variant is predicted to disrupt the canonical splice donor site in intron 4 resulting in skipping of exon 4. This is expected to cause a frameshift with premature stop at codon 122 (exon 5 of 15), therefore NMD would be expected.
• PM2_Supporting: Absent in gnomADv4.1 database (PM2_supporting).

Not Met criteria codes

• PP1: The homozygous c.614+1G>T and Arg288His variants were seen to segregate in two affected members of a family with GT. (PMID: 25728920) Patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.
• PP4: Two related individuals(GT43a&b) had history of significant mucocutaneous bleeding, platelet aggregation was absent 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)
• PM3: The ITGB3 c.614+1G>T and Arg228His variants were found in homozygous state in two related members of a family with GT. 0.5 points. However, since patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.