Variant: NM_000212.3:c.777+1G>A

CA8623036

850886 (ClinVar)

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: e4899cc1-99c5-43c2-9c95-ac0668ade48f

Approved on: 2021-03-05

Published on: 2021-08-20

HGVS expressions

NM_000212.3:c.777+1G>A
NC_000017.11:g.47286423G>A
CM000679.2:g.47286423G>A
NC_000017.10:g.45363789G>A
CM000679.1:g.45363789G>A
NC_000017.9:g.42718788G>A
NG_008332.2:g.37582G>A
ENST00000559488.7:c.777+1G>A
ENST00000559488.5:c.777+1G>A
ENST00000560629.1:n.742+1G>A
ENST00000571680.1:c.777+1G>A
NM_000212.2:c.777+1G>A

Pathogenic

• Met criteria codes: PP1 PP4_Strong PVS1

• Not Met criteria codes: PP3 PM3 PM2

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.3(ITGB3):c.777+1G>A is a canonical splice donor variant which is predicted to cause skipping of exon 5, with a frameshift resulting in NMD. It has been reported to occur in one homozygous and one compound heterozygous proband, and at least one of those individuals satisfies clinical and laboratory criteria for GT phenotype (PMID: 25728920). This variant was reported to co-segregate in at least two affected members of a family (PMID: 25728970). This variant meets GT specific criteria for PVS1, PP4_strong, and PP1 and is therefore classified as Pathogenic.

Met criteria codes

• PP1: c.777+1G>A variant has been reported to segregate in one proband (GT35a) plus one affected relative (sister - GT35b) in PMID 25728920. Both siblings are compound heterozygous for c.777+1G>A and Arg131Pro. Meets criteria for PP1_supporting.
• PP4_Strong: This variant has been reported in 3 probands by PMID 25728920. And at least one proband (GT30) meets criteria for PP4_Strong - which includes history of significant mucocutaneous bleeding, absent platelet aggregation with physiological agonists except ristocetin, flowcytometric demonstration of reduced (<5%)surface expression of αIIbβ3 expression. Sanger sequencing was done to ensure full coverage of all exons and intron of the IGTB3 and ITGA2B genes. ( PMID:25728920) PP4_strong applied
• PVS1: c.777+1G>A is a canonical splice donor variant which is predicted to cause skipping of exon 5 of 15, causing a frameshift with a premature stop codon in exon 6, leading to NMD.

Not Met criteria codes

• PP3: Multiple insilico splicing tools(maxentscan,spliceAI) predict this variant to cause disruption of the canonical splice donor site and exon 5 skipping. However since PVS1 has been applied, PP3 is not applied here.
• PM3: The c.777+1G>A variant was reported in two probands in PMID:25728920, one in the homozygous state (GT30) and one in the compound heterozygous state (GT35a) along with a missense variant (p.Arg131Pro). PM3 cannot be applied here because PM2_supporting is not met.
• PM2: Although the overall allele frequency in gnomAD is 0.00008560 (24/280376), the MAF in the Latino subpopulation is 0.0006774 (24/35432), which is above the threshold of <0.01%. Therefore, PM2_supporting is not met.