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_000212.3:c.361+1G>A

CA400021329

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5160e951-527b-4568-9c40-fcdc1f3ea0a5

HGVS expressions

NM_000212.3:c.361+1G>A

NC_000017.11:g.47283550G>A

CM000679.2:g.47283550G>A

NC_000017.10:g.45360916G>A

CM000679.1:g.45360916G>A

NC_000017.9:g.42715915G>A

NG_008332.2:g.34709G>A

ENST00000559488.7:c.361+1G>A

ENST00000559488.5:c.361+1G>A

ENST00000560629.1:n.326+1G>A

ENST00000571680.1:c.361+1G>A

NM_000212.2:c.361+1G>A

Pathogenic

PP4_Moderate PM2_Supporting PVS1

PM3

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.3(ITGB3):c.361+1G>A occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3/15, resulting in a frameshift (p.Ala56Metfs*23) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). GT3 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.61%, as measured by flow cytometry. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PP3. (VCEP specifications version 2; date of approval 09/02/2021).

PP4_Moderate

GT3 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.61% (<25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PVS1

The c.361+1G>A variant in ITGB3 occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3/15, resulting in a frameshift (p.Ala56Metfs*23) leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PM3

GT3 is compound heterozygous for c.361+1G>A and Gly564Arg (classified VUS by the PD VCEP). This variant is not scored here to avoid circularity.

Approved on: 2021-09-03

Published on: 2021-12-23

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.