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_000419.5:c.2063C>T

CA399799766

1210185 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 08d0d385-0175-4f6f-b39b-c1f635eba146

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000419.5:c.2063C>T

NC_000017.11:g.44378393G>A

CM000679.2:g.44378393G>A

NC_000017.10:g.42455761G>A

CM000679.1:g.42455761G>A

NC_000017.9:g.39811287G>A

NG_008331.1:g.16113C>T

ENST00000262407.6:c.2063C>T

ENST00000648408.1:c.1494C>T

ENST00000262407.5:c.2063C>T

ENST00000592462.5:n.858C>T

NM_000419.3:c.2063C>T

NM_000419.4:c.2063C>T

Likely Pathogenic

PM3_Supporting PP4_Strong PM2_Supporting

BP4 PP3

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 ITGA2B missense variant NM_000419.5:c.2063C>T replaces the alanine residue with a valine residue (p.Ala688Val). This variant is very rare in control population databases; the highest population minor allele frequency in gnomAD v4.1.0 is 0.00003332 (2/60020 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). It has been observed in homozygosity in one individual (Case 36 in PMID: 28983057; PM3_supporting) with a phenotype specific for Glanzmann's thrombasthenia (GT). Case 36 (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; markedly reduced expression of GPIIb/IIIa (confirmed to be <20% by personal communication with author); direct sequencing of all exons, untranslated regions, and flanking regions of ITGA2B and ITGB3. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporting, PP4_strong.

PM3_Supporting

This variant was observed in homozygosity in one individual (Case 36 in PMID: 28983057), earning 0.5 points and sufficient to apply PM3_supporting.

PP4_Strong

This variant was reported in homozygosity in one individual (Case 36 in PMID: 28983057) who 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; markedly reduced expression of GPIIb/IIIa (confirmed to be <20% compared to controls by personal communication with author Dr. Jose Rivera); direct sequencing of all exons, untranslated regions, and flanking regions of ITGA2B and ITGB3.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003332 (2/60020 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).

BP4

See explanation for PP3.

PP3

The REVEL score for this variant is 0.394, below the VCEP-established threshold of ≥0.7 to apply PP3 and above the VCEP-established threshold of <0.25 to apply BP4. Additionally, splice predictors (SpliceAI and MaxEntScan) do not predict a damaging effect on splicing.

Curation History

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