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_000419.3(ITGA2B):c.1787T>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA115846

2900 (ClinVar)

Gene: N/A

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c6b42f33-92f7-4a71-822b-932469bd66ae

Approved on: 2023-10-17

Published on: 2023-10-17

HGVS expressions

NM_000419.3(ITGA2B):c.1787T>C

NC_000017.11:g.44379780A>G

CM000679.2:g.44379780A>G

NC_000017.10:g.42457148A>G

CM000679.1:g.42457148A>G

NC_000017.9:g.39812674A>G

NG_008331.1:g.14726T>C

ENST00000262407.6:c.1787T>C

ENST00000648408.1:c.1218T>C

ENST00000262407.5:c.1787T>C

ENST00000592462.5:n.582T>C

NM_000419.3:c.1787T>C

NM_000419.4:c.1787T>C

NM_000419.5:c.1787T>C

Pathogenic

PP1 PM3_Strong PP4_Strong

PP3 PM2

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr) missense variant has been reported in the homozygous state in at least 2 apparently unrelated individuals (PMID: 22513797, 20020534) and in the compound heterozygous state in 4 individuals (PMID: 9215749, 9734640, 34552732, 25373348). The second variants in these patients are c.3060+2T>C (classified Pathogenic by the PD-VCEP; without confirmation of trans phase), Glu355Lys (classified Pathogenic by the PD-VCEP; with confirmation of trans phase), c.2841+1G>T, and c.408G>C (latter two not considered here to avoid circularity) respectively (PM3_Strong). The proband from PMID: 22513797 meets criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3. It was found to co-segregate with disease in 1 additional family member (PP1). In summary, this variant is classified Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific codes applied: PP4_Strong, PM3_Strong, PP1. (PD-VCEP specifications version 2)

PP1

Patient 3 is the 16yo sister of the proband, Patient 4. Both siblings are diagnosed with GT, homozygous for the variant and meet phenotype criteria, thus meeting PP1

PM3_Strong

This variant has a Popmax filtering allele frequency of 0.00008137 so the PD-VCEP has considered it sufficiently rare for inclusion in the PM3 criteria. The variant has been observed in the homozygous state in at least 2 apparently unrelated individuals (PMID: 22513797, 20020534; 1pt) and in the compound heterozygous state in 4 individuals (PMID: 9215749, 9734640, 34552732, 25373348). The second variants in these patients are c.3060+2T>C (classified Pathogenic by the PD-VCEP without confirmation of trans phase 0.5pt), Glu355Lys (classified Pathogenic by the PD-VCEP with confirmation of trans phase 1pt), c.2841+1G>T, and c.408G>C (latter two not considered here to avoid circularity) respectively. Total 2.5pt; PM3_Strong

PP4_Strong

Proband from PMID: 22513797 meet criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3.

PP3

In-silico evidence is available from PMID: 29385657: the authors suggest that Ile596 is a likely mutational hot spot; it is relatively well conserved both between species and within human α‐subunits. They report that the Thr introduces an ‐OH alcoholic function close to Arg551, which competes for H‐bonds with residues Asp542, Ser594 and Asp591 changing interatom distances and creating an additional H‐bond within connecting loops extending from the lower region of the thigh. However, the Ile596Thr variant has a REVEL score <0.7: 0.628.

PM2

Ile596Thr is reported in gnomAD v3 (non v2) at a frequency of 0.0001156 (6/51922 non-Finnish European alleles), and in gnomAD v2.1.1, at a frequency of 0.0001325 (15/113200 non-Finnish European alleles). Both separate and combined (non-Finnish European population, 0.000127) frequency estimates for this variant exceed the PM2 threshold of <1 in 10000 alleles. The Popmax filtering allele frequency is 0.00008137 and would meet this requirement, this will be considered by the PD-VCEP for future specification updates.

Curation History

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