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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000419.5:c.3076_3077delinsGC

CA915940802

996160 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8cea0ef5-f56f-4085-b6f3-6d539ea6797a

HGVS expressions

NM_000419.5:c.3076_3077delinsGC

NC_000017.11:g.44372407_44372408delinsGC

CM000679.2:g.44372407_44372408delinsGC

NC_000017.10:g.42449775_42449776delinsGC

CM000679.1:g.42449775_42449776delinsGC

NC_000017.9:g.39805301_39805302delinsGC

NG_008331.1:g.22098_22099delinsGC

ENST00000262407.6:c.3076_3077delinsGC

ENST00000648408.1:c.2390_2391delinsGC

ENST00000262407.5:c.3076_3077delinsGC

ENST00000587295.5:c.269_270delinsGC

ENST00000588098.1:c.53_54delinsGC

NM_000419.3:c.3076_3077delinsGC

NM_000419.4:c.3076_3077delinsGC

NM_000419.5(ITGA2B):c.3076_3077delinsGC (p.Arg1026Ala)

Uncertain Significance

PM2_Supporting

BP4 PS3 PP3 PP4 PM5

Evidence Links 1

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:c.3076_3077delinsGC results in a missense change, Arg1026Ala. The variant is absent gnomAD v2.1.1 and v3. PMID: 12575292 reports on the variant, but the evidence does not meet GT criteria for phenotype or functional studies. In summary, there is insufficient evidence at this time to classify this variant. GT-specific criteria met: PM2_Supporting.

PM2_Supporting

The variant is absent from gnomAD v2.1.1 and v3, meeting criteria for PM2.

BP4

There is no predicted impact on canonical splice sites however HSF predicts significant alteration of ESE / ESS motifs ratio (-5).

PS3

Evidence from PMID: 12575292 suggests that the Arg1026Ala variant could result in constitutively active platelets. PS3 criteria not met. Similar results are reported in PMID: 35766979

(Article in Chinese) Authors report on CHO cells were transfected with wild-type or mutant (Arg1026Ala) ITGA2B cDNA. When cells were not activated, wild-type αⅡbβ3-expressing cells failed to bind PAC-1, but could adhere fibrinogen; however, mutant-expressing CHO cells were able to bind PAC-1 and showed high-affinity fibrinogen binding, suggesting an inside-out signaling defect. PubMed:12575292

PP3

A REVEL score is not available for this variant however the amino acid change Arg1026Ala is predicted deleterious by PolyPhen (1.000, probably damaging), fthmm (-9.24, damaging), and PROVEAN (-4.939, deleterious).

PP4

Only one patient reported in PMID: 12575292. It is unclear if the patient indeed had the Arg1026Ala variant and experimental evidence from this paper suggests the variant causes platelets to be constitutively active. PP4 criteria not met.

PM5

Arg1026Gln and Arg1026Trp occur at the same residue but have been evaluated as a VUS in relation to Glanzmann's Thrombasthenia by the Platelet Disorders VCEP.

Approved on: 2023-11-02

Published on: 2023-11-03

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.