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]

Variant: NM_000212.2(ITGB3):c.985A>G (p.Asn329Asp)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA8623107

323865 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 99836e69-f8b5-45a8-8e8a-14b22acd4d46

Approved on: 2024-01-04

Published on: 2024-01-05

HGVS expressions

NM_000212.2:c.985A>G

NM_000212.2(ITGB3):c.985A>G (p.Asn329Asp)

NC_000017.11:g.47289726A>G

CM000679.2:g.47289726A>G

NC_000017.10:g.45367092A>G

CM000679.1:g.45367092A>G

NC_000017.9:g.42722091A>G

NG_008332.2:g.40885A>G

ENST00000696963.1:c.985A>G

ENST00000559488.7:c.985A>G

ENST00000559488.5:c.985A>G

ENST00000560629.1:c.950A>G

ENST00000571680.1:c.985A>G

NM_000212.3:c.985A>G

Uncertain Significance

PP3 BS1

PP4 PM3

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.985A>G replaces the asparagine residue with an aspartic acid residue (p.Asn329Asp). This variant has been observed in heterozygosity in two individuals suspected to have Glanzmann's thrombasthenia (GT) (GT-73 and GT-74 in PMID: 30792900), however sufficient information to confirm if the individuals' phenotypes are specific for GT was not provided and a second ITGB3 variant was not identified in either proband. In silico tools predict the variant is damaging to protein function (REVEL score of 0.911; PP3). The highest population minor allele frequency in gnomAD v4.0.0 is 0.003123 (19/6084 alleles) in the Middle Eastern population, which is higher than the ClinGen PD VCEP BS1 threshold (>0.00158). In summary, this variant is of uncertain significance. GT-specific criteria applied: BS1, PP3.

PP3

REVEL score of 0.911 is above the >0.7 threshold to support a deleterious effect.

BS1

The highest population minor allele frequency in gnomAD v4.0.0 is 0.003123 (19/6084 alleles) in the Middle Eastern population, which is higher than the ClinGen PD VCEP BA1 threshold (>0.0024), due to this being a bottle-necked population this was downgraded to BS1. The next highest minor allele frequency in gnomAD v4.0.0 is 0.0003471 (26/74916 alleles) in the African/African-American population.

PP4

This variant has been observed in two individuals with a previous history of type III or variant Glanzmann thrombasthenia (GT-73 and GT-74 in PMID: 30792900), but sufficient phenotypic details, platelet aggregation information, and protein surface expression information were not provided to apply PP4 at any strength level.

PM3

This variant was identified in heterozygosity in two probands (GT-73 and GT-74, PMID: 30792900) with no second ITGB3 variant identified. PM3 could not be applied at any strength level for these heterozygous occurrences.

Curation History

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