Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

CA123252

13567 (ClinVar)

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

ENST00000559488.7:c.428T>G

ENST00000559488.5:c.428T>G

ENST00000560629.1:n.393T>G

ENST00000571680.1:c.428T>G

NM_000212.3:c.428T>G

Likely Pathogenic

PP4_Moderate PS3 PP1 PP3

PM3 PM2

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

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 13 individuals suspected to have Glanzmann's thrombasthenia (GT) (PMID: 9376589, PMID: 26096001, PMID: 16463284), at least one of which has a phenotype specific for GT (Patient MK, PMID: 9376589). This variant has also been observed to segregate with disease in two affected family members (Patients L and M, PMID: 26096001). Additionally, in silico tools predict the variant is damaging to protein function 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). However, the population frequency of this variant is above the threshold to apply PM2_supporting and it may be a founder variant in Indian populations (PMID: 16463284). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3, PP4_moderate, PP1, PP3.

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.

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.

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. PubMed:11806996

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

Although this variant has been observed in homozygosity at least 13 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) and in heterozygosity in one individual (GT-09, PMID: 16463284), PM3 was not applied because the variant is not sufficiently rare to meet the criterion to apply PM2.

PM2

This variant was observed in heterozygosity in five individuals in gnomAD v2.1.1 (MAF in Other population: 0.0001629 (1/6138 alleles) and in South Asian population: 0.0001307 (4/30614 alleles); overall allele frequency: 0.00001988 (5/251478 alleles)). Although this variant is relatively rare in control population databases, the frequency in both the Other and South Asian populations is above the VCEP-established threshold of fewer than 1 in 10,000 alleles and the criterion to apply PM2_supporting is not met. PMID: 16463284 suggests this variant is a founder variant in Indian populations.

Approved on: 2021-02-10

Published on: 2021-08-20

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