NM_000419.5:c.1413C>G

CA290950376

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 09f57705-bbc6-4b9a-9251-3f7edd5614ba

Approved on: 2020-09-06

Published on: 2021-01-28

HGVS expressions

NM_000419.5:c.1413C>G
NM_000419.3:c.1413C>G
NM_000419.4:c.1413C>G
ENST00000262407.5:c.1413C>G
ENST00000592226.5:n.886C>G
ENST00000592462.5:n.208C>G
NC_000017.11:g.44380626G>C
CM000679.2:g.44380626G>C
NC_000017.10:g.42457994G>C
CM000679.1:g.42457994G>C
NC_000017.9:g.39813520G>C
NG_008331.1:g.13880C>G

Pathogenic

• Met criteria codes: PVS1 PP4_Strong PM2_Supporting PM3_Supporting

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGA2B nonsense variant NM_000419.4:c.1413C>G (p.Tyr471Ter) introduces a premature termination codon and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in a proband with a phenotype specific for Glanzmann's thrombasthenia (GT) who also harbors a second ITGA2B variant (c.1882C>T, p.Arg628Ter) previously classified by the VCEP as pathogenic. Furthermore, this variant has been reported in low frequencies in population databases (<1/10,000 alleles in gnomAD). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3_supporting, and PP4_strong.

Met criteria codes

• PVS1: This variant introduces a termination codon at amino acid position 471 in exon 14/30. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function.
• PP4_Strong: All requirements for PP4 at an upgraded strength of moderate (PP4_Strong) are met: GI bleeding; total lack of platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed <5% expression of αIIbβ3; direct sequencing of all exons and splice sites of ITGA2B and ITGB3, as well as upstream regions.
• PM2_Supporting: This variant is present in gnomAD v2.1.1 with a MAF of 0.000008791 (1/113756 alleles; non-Finnish European population) and an overall allele frequency of 0.000003977. This low frequency is below the prevalence threshold of <1/10,000 alleles and meets PM2.
• PM3_Supporting: This variant has been observed in combination with the VCEP-curated pathogenic ITGA2B variant c.1882C>T (p.Arg628Ter) in 1 proband (PMID: 20492470; same proband also reported in PMID: 29884513, PMID: 25728920 (GT25), and PMID: 27469266). However, the phase of these two variants was not confirmed. This occurrence with phase unknown scores 0.5 points, meeting PM3 at the downgraded strength level of supporting (PM3_supporting). This variant was also observed in combination with p.Gly823Glu (PMID 25728920), p.Val934Phe (PMID 20020534), p.Gly1007TrpfsTer29 (PMID 9798966), and a large deletion of exons 23-29 (PMID 25728920). However, this evidence contributed or could contribute to PM3 in the classification of p.Gly823Glu, p.Val934Phe, p.Gly1007TrpfsTer29, and the exon 23-29 intragenic deletion and was not counted for p.Tyr471Ter to avoid circularity.