NM_000419.5:c.2748_2757del

CA290946532

996173 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: bac82a5d-576c-4012-be40-8e6e75a437dc

Approved on: 2020-10-20

Published on: 2021-01-22

HGVS expressions

NM_000419.5:c.2748_2757del
NC_000017.11:g.44375084_44375093del
CM000679.2:g.44375084_44375093del
NC_000017.10:g.42452452_42452461del
CM000679.1:g.42452452_42452461del
NC_000017.9:g.39807978_39807987del
NG_008331.1:g.19415_19424del
ENST00000262407.6:c.2748_2757del
ENST00000648408.1:c.2179_2188del
ENST00000262407.5:c.2748_2757del
ENST00000587295.5:c.253+742_253+751del
ENST00000592462.5:n.2022_2031del
NM_000419.3:c.2748_2757del
NM_000419.4:c.2748_2757del

Pathogenic

• Met criteria codes: PP4_Strong PVS1_Strong PM2_Supporting PM3

• Not Met criteria codes: PM4

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGA2B frameshift variant NM_000419.5:c.2748_2757del (p.Thr917SerfsTer?) leads to a frameshift and alteration of the coding sequence of the transmembrane domain, a region of the protein critical for ITGA2B function. This variant has been observed in homozygosity in two individuals, at least one of which was reported to have a phenotype specific for Glanzmann's Thrombasthenia (GT). This variant is rare in population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1_strong, PM3, PP4_strong, PM2_supporting.

Met criteria codes

• PP4_Strong: This variant was reported in homozygosity in two individuals (CabGT-14, PMID: 20020534 and the proband reported in the dissertation published by Celia Garijo Pacheco (University of Vallodolid; https://core.ac.uk/download/pdf/211107058.pdf). At least one of these individuals (proband described in Pacheco Dissertation) meets all requirements for PP4 at an upgraded strength of strong (PP4_Strong): bleeding symptoms including epistaxis, petechiae, hematoma, and gingival bleeding; absent platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed absent expression of αIIb and β3; next-generation sequencing of ITGA2B and ITGB3.
• PVS1_Strong: This variant introduces a frameshift in exon 27/30, altering the remainder of the coding sequence, including the transmembrane domain (spanning amino acids 994-1019) considered critical to protein function. The frameshift is also predicted to abolish the stop codon and add an 57 extra amino acid residues to the coding sequence.
• PM2_Supporting: This variant is rare in population databases. In gnomAD v2.1.1 the variant was observed in 1/8692 alleles in the African population and 1/31328 alleles in the overall population. In gnomAD v3, the variant was observed in 3/41998 alleles in the African population and 3/143408 alleles in the overall population. PM2_Supporting is applied based on the frequency reported in the gnomAD v3 African population, which is below the 1/10000 allele threshold.
• PM3: This variant was reported in homozygosity in two individuals (CabGT-14 in PMID: 20020534 and the proband reported in the dissertation published by Celia Garijo Pacheco (University of Vallodolid; https://core.ac.uk/download/pdf/211107058.pdf)). Each homozygous occurrence earns 0.5 points for a total of 1 point, sufficient to apply PM3.

Not Met criteria codes

• PM4: This variant is predicted to result in loss of the stop codon and extension of the coding sequence by 57 amino acid residues. However, PM4 was not applied in combination with PVS1 in order to avoid double counting this evidence.