Evidence Repository - Clinical Genome Resources

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Variant: NM_000212.2(ITGB3):c.428T>G (p.Leu143Trp)

CA123252

13567 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ce6d64be-3f9d-41cb-ada5-71ebdf8c6cb9

Approved on: 2024-06-06

Published on: 2024-06-07

HGVS expressions

NM_000212.2:c.428T>G

NM_000212.2(ITGB3):c.428T>G (p.Leu143Trp)

NC_000017.11:g.47284509T>G

CM000679.2:g.47284509T>G

NC_000017.10:g.45361875T>G

CM000679.1:g.45361875T>G

NC_000017.9:g.42716874T>G

NG_008332.2:g.35668T>G

ENST00000696963.1:c.428T>G

ENST00000559488.7:c.428T>G

ENST00000559488.5:c.428T>G

ENST00000560629.1:c.393T>G

ENST00000571680.1:c.428T>G

NM_000212.3:c.428T>G

Pathogenic

PP4_Moderate PM2_Supporting PS3 PP1 PP3 PM3

BS1 PM5

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGB3 missense variant NM_000212.2:c.428T>G replaces the leucine residue with a tryptophan residue (p.Leu143Trp). This variant has been observed in homozygosity in at least 14 individuals reported to have Glanzmann's thrombasthenia (GT) (PMID: 9376589, PMID: 26096001, PMID: 16463284, PMID: 36672149; PM3). PMID: 16463284 suggests this variant is a founder variant in Indian populations. At least one patient has a phenotype specific for GT (Patient MK, PMID: 9376589) with a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Additionally, flow cytometry showed <10% expression of αIIbβ3 (PP4_Moderate). This variant has also been observed to segregate with disease in two affected family members (Patients L and M, PMID: 26096001; PP1). Additionally, in silico tools predict the variant is damaging to protein function (REVEL score 0.98; PP3) and transient expression of ITGB3 carrying the variant in 293 cells led to a reduced level of αIIbβ3 and αIIb receptor expression on the cell surface (<5% compared to cells expressing wild type ITGB3, PMID: 11806996; PS3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009881 (9/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PS3, PP4_moderate, PP1, PP3, PM2_supporting, PM3.

PP4_Moderate

All requirements for PP4_moderate are met (Patient MK, PMID: 9376589): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Additionally, flow cytometry showed <10% expression of αIIbβ3, however full sequencing of intron-exon boundaries of ITGA2B and ITGB3 was not performed.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009881 (9/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). PMID: 16463284 suggests this variant is a founder variant in Indian populations.

PS3

PMID: 11806996: ITGB3 cDNA carrying the c.428T>G variant and wild type ITGA2B cDNA were transiently co-transfected into 293 cells. αIIbβ3 and αIIb receptor expression on the cell surface was measured by flow cytometry and immunoprecipitation and both were shown to be reduced to <5% compared to wild type.

PP1

This variant was observed in homozygosity in a proband (Patient L in PMID: 26096001) and their affected sibling (also in homozygosity; Patient M in PMID: 26096001).

PP3

REVEL score of 0.98 is above the >.0.7 threshold, in support of a deleterious effect.

PM3

This variant has been observed in homozygosity at least 14 individuals (Patient MK, PMID: 9376589; Patient L, PMID: 26096001; GT-08, GT-16, GT-32, GT-33, GT-39, GT-40, GT-48, GT-50, GT-53, GT-60-1, GT-64, PMID: 16463284, PMID: 36672149 pt 13) and in compound heterozygosity in one individual (GT-09, PMID: 16463284), PM3

BS1

The highest MAF in gnomAD v4.0.0 is 0.0001043 (9/86258 alleles) in the South Asian population which is above the <0.0001 threshold for PM2_supporting but below the <0.00158 threshold for BS1. PMID: 16463284 suggests this variant is a founder variant in Indian populations.

PM5

Another missense variant NM_000212.3(ITGB3):c.428T>C (p.Leu143Ser) in the same codon has been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP but is not considered here to avoid circularity.

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