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_000419.4(ITGA2B):c.1234G>A (p.Gly412Arg)

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CA8603182

381748 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d5a47ada-b724-415e-a81e-5d8e8e2fa322

Approved on: 2021-12-23

Published on: 2021-12-23

HGVS expressions

NM_000419.4:c.1234G>A

NM_000419.4(ITGA2B):c.1234G>A (p.Gly412Arg)

NC_000017.11:g.44381038C>T

CM000679.2:g.44381038C>T

NC_000017.10:g.42458406C>T

CM000679.1:g.42458406C>T

NC_000017.9:g.39813932C>T

NG_008331.1:g.13468G>A

ENST00000262407.6:c.1234G>A

ENST00000648408.1:n.665G>A

ENST00000262407.5:c.1234G>A

ENST00000592226.5:n.474G>A

ENST00000592462.5:n.29G>A

NM_000419.3:c.1234G>A

NM_000419.5:c.1234G>A

NM_000419.5(ITGA2B):c.1234G>A (p.Gly412Arg)

Pathogenic

PP4_Strong PM2_Supporting PM3_Strong

PP3

Evidence Links 6

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.1234G>A (p.Gly412Arg) variant has been reported in at least six GT patients in the literature; at least 4 of them (from PMIDs: 29675921, 24418945, 19691478, 21557682) with a phenotype highly specific to GT. This includes 2 homozygotes and 4 compound heterozygotes. The variant is found at an extremely low frequency, with an the overall allele frequency on gnomAD is 0.00010 (5/49256) alleles in the Latino population). In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PM3_Strong, PM2_Supporting, and PP4_Strong.

PP4_Strong

At least six GT patients have been described in the literature with the Gly412Arg variant, at least 1 of which (PMID: 29675921) meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

This proband meets all the GT criteria. Patient GT19, a homozygote, had bleeding phenotypes including epistaxis, gingival bleeding, hematuria, post traumatic hemorrhage, menorrhagia , and a bleeding score of 4. There was a normal platelet count. Aggregation was absent in response to ADP and collagen but normal in response to ristocetin. The patient was reported to have type 1 GT with <5% αIIbβ3 expression by flow cytometry. PubMed:29675921

The proband meets all the GT criteria. Patient GT37, a homozygote, was reported to have type 1 GT based on severely reduced expression of αIIb‐β3 on the platelets by flow cytometry. The patient had a history of mucocutaneous bleeding, platelet count was normal, and platelet aggregation revealed absent/reduced aggregation in response to ADP, ADR, AA, and collagen but normal aggregation with ristocetin. PubMed:19691478

Patient FO, a compound heterozygote, was reported to have type I GT with a lack of GpIIb-GPIIIa at the platelet surface (by Western blot and flow cytometry). GT diagnosis was reportedly evoked on clinical presentation and platelet aggregation analysis (patient specific details, such as bleeding phenotype, platelet count, and aggregometry were not provided). PubMed:11798398

This article reported that all included GT patients had normal platelet counts and abnormal aggregation (a normal response to ristocetin was not noted). Flow cytometry was performed by the results were not provided for each patient nor were bleeding phenotypes reported. PubMed:27607598

The proband meets all the GT criteria. A normal platelet count is reported and bleeding phenotypes include epistaxis, gingivorrhagia, easy bruising, menorrhagia, bleeding after tooth extraction, haemorrhage after surgery and haemarthrosis. Aggregometry results showed failure of ADP, collagen and adrenalin to induce platelet aggregation, but ristocetin-induced platelet aggregation (RIPA) was normal. Platelet surface glycoprotein analysis by flow cytometry revealed a severe αIIbβ3 deficiency (<10% according to Glanzmann Thrombasthenia database record 325). PubMed:24418945

The proband meets all the GT criteria. Bleeding symptoms include epistaxis, menorrhagia, spontaneous hematoma, and purpura (reported in PMID: 3762006). She has a normal platelet count, absent aggregation to ADP, arachidonic acid and collagen but a normal ristocetin response (reported in PMID: 25728920). There is 10-15% surface expression of αIIb‐β3 on the platelets (reported in review PMID: 23929305 and as GT11 in PMID: 25728920) with residual protein by Western blot. PubMed:21557682

PM2_Supporting

The overall allele frequency in gnomADv2 is 0.00003234 with an MAF of 0.0001453 in the Latino population (5/34,414 alleles) an additional 14,842 Latino alleles in gnomADv3 do not have this variant for an overall MAF of 0.000102 (5/49256) for the combined data (which was considered consistent with the VCEP established threshold of <0.0001).

PM3_Strong

The Gly412Arg variant has been reported multiple times in the literature; twice in the homozygous state, and once each in trans with c.1214T>C (p.Ile405Thr), c.1073G>A (p.Arg358His), and c.2153dupG which are classified as Pathogenic by the ClinGen Platelet Disorders VCEP. It has also been observed once in trans with c.641T>C (p.Leu214Pro) which has been classified as Likely Pathogenic by the ClinGen Platelet Disorders VCEP.

Patient GT19 is homozygous (without parental consanguinity) for the c.1234G>A (p.Gly412Arg) variant. 0.5pt PubMed:29675921

Patient GT37 is homozygous for Gly412Arg (the homozygous state of this patient is reported in PMID: 25275492). 0.5pt PubMed:19691478

Patient FO is compound heterozygous for the Pathogenic variant c.2153dupG (p.Cys718Trpfs*2) and c.1234G>A (p.Gly412Arg). The trans phase of the variants was not confirmed. 0.5pt PubMed:11798398

The genotype was reported for one of the six Glanzmann Thrombasthenia patients; this patient was a compound heterozygote for the Pathogenic variant c.641T>C (p.Leu214Pro) and c.1234G>A (p.Gly412Arg). The variants were confirmed to be in trans by parental testing. 1pt PubMed:27607598

The proband is reported to be compound heterozygous for the Pathogenic variant c.1214T>C (p.Ile405Thr) and c.1234G>A (p.Gly412Arg) however confirmation of the trans phasing is not reported. 0.5 pt PubMed:24418945

The proband is compound heterozygous for the paternally inherited Likely Pathogenic variant c.1073G>A (p.Arg358His) variant and the maternally inherited c.1234G>A (p.Gly412Arg) variant. 1pt PubMed:21557682

PP3

SIFT (damaging), PolyPhen (probably damaging), and MutationTaster (disease causing) support a deleterious effect, however the REVEL score of 0.566 is below the VCEP established threshold of >0.7. Additionally, HumanSplicingFinder (44.99% variation) and MaxEntScan (328.51% variation) agree that there is activation of an exonic cryptic acceptor site with potential alteration of splicing which could cause loss of 25 amino acids. However, there is no predicted effect on canonical splice sites.

Curation History

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