NM_000212.3:c.431T>G

CA291224645

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 862523d6-6c86-4068-aecb-c9e5446d8fb8

Approved on: 2021-04-20

Published on: 2021-08-20

HGVS expressions

NM_000212.3:c.431T>G
NC_000017.11:g.47284512T>G
CM000679.2:g.47284512T>G
NC_000017.10:g.45361878T>G
CM000679.1:g.45361878T>G
NC_000017.9:g.42716877T>G
NG_008332.2:g.35671T>G
ENST00000559488.7:c.431T>G
ENST00000559488.5:c.431T>G
ENST00000560629.1:n.396T>G
ENST00000571680.1:c.431T>G
NM_000212.2:c.431T>G

Pathogenic

• Met criteria codes: PP1 PP3 PM3 PM2_Supporting PS3_Supporting PP4_Strong

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGB3 missense variant NM_000212.3:c.431T>G replaces the methionine residue with an arginine residue (p.Met144Arg). This variant is very rare in control population databases, but has been observed in homozygosity in four individuals suspected to have Glanzmann's thrombasthenia (GT) (CabGT-22 in PMID: 20020534; GT-7 in PMID: 25539746; Case 39 in PMID: 28983057; Case 18-086 reported by personal communication from Dr. José Rivera, Universidad de Murcia). At least one of these individuals (Case 39 in PMID: 28983057) has a phenotype specific for GT and an affected sibling also homozygous for the variant. The variant is predicted by in silico tools to be damaging to protein function and the functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-17% compared to wild type; PMID: 20020534). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PM3, PP1, PP3, PP4_strong.

Met criteria codes

• PP1: This variant was observed in homozygosity in the original proband (Case 39 in PMID: 28983057) and an affected sibling (also in homozygosity) (personal communication from Dr. José Rivera, Universidad de Murcia, corresponding author of PMID: 28983057).
• PP3: The REVEL score for this variant is 0.946, exceeding the VCEP-established threshold of ≥ 0.7 to apply PP3.
• PM3: This variant was reported in homozygosity in four individuals (CabGT-22 in PMID: 20020534; GT-7 in PMID: 25539746; Case 39 in PMID: 28983057; Case 18-086 reported by personal communication from Dr. José Rivera, Universidad de Murcia), earning 2 points. However, the overall score for these homozygous occurrences was limited to 1 point to prevent overclassification of homozygous occurrences in the absence of additional data and is sufficient to apply PM3.
• PM2_Supporting: This variant is rare in control population databases. It was not observed in gnomAD v2.1.1 and was observed in heterozygosity in a single individual in gnomAD v3 (MAF in African population: 0.00002380 (1/42016 alleles); overall allele frequency: 0.000006980 (1/143272 alleles)). This frequency is below the VCEP-established threshold of fewer than 1 in 10,000 alleles, meeting the criterion to apply PM2_supporting.
• PS3_Supporting: PMID: 20020534: ITGB3 cDNA carrying the c.431T>G variant was transiently transfected into COS-7 cells. αIIb, β3, and αIIbβ3 receptor expression on the cell surface was measured by flow cytometry. The number of cells positive for αIIb, β3, and αIIbβ3 was found to be reduced (estimated to be ~7-17% compared to wild type). This evidence was downgraded to PS3_Supporting because the level of αIIb, β3, and αIIbβ3 cell surface expression was not reported, only whether cells were positive or negative for surface αIIb, β3, and αIIbβ3.
• PP4_Strong: This variant was reported in homozygosity in four individuals (CabGT-22 in PMID: 20020534; GT-7 in PMID: 25539746; Case 39 in PMID: 28983057; Case 18-086 reported by personal communication from Dr. José Rivera, Universidad de Murcia). At least one of these individuals (Case 39 in PMID: 28983057) meets all requirements for PP4 at an upgraded strength of strong (PP4_strong): bleeding phenotype strongly indicative of Glanzmann's thrombasthenia; impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin; 15% expression of GPIIb/IIIa; direct sequencing of all exons, untranslated regions, and flanking regions of ITGA2B and ITGB3.