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]

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Variant: NM_000212.3:c.353T>A

CA291224511

996166 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0b50ce4a-11b2-4ebd-a950-73091ce0fb3b

HGVS expressions

NM_000212.3:c.353T>A

NC_000017.11:g.47283541T>A

CM000679.2:g.47283541T>A

NC_000017.10:g.45360907T>A

CM000679.1:g.45360907T>A

NC_000017.9:g.42715906T>A

NG_008332.2:g.34700T>A

ENST00000559488.7:c.353T>A

ENST00000559488.5:c.353T>A

ENST00000560629.1:c.318T>A

ENST00000571680.1:c.353T>A

NM_000212.2:c.353T>A

NM_000212.3(ITGB3):c.353T>A (p.Leu118His)

Likely Pathogenic

PP4_Strong PM3_Supporting PM2_Supporting PP3

PS3

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

NM_000212.3(ITGB3):c.353T>A (p.Leu118His) is a missense variant that is absent from large population cohorts, including gnomADv2.1.1 (PM2_supporting). It has been reported in at least one proband who meets the diagnostic criteria for the GT phenotype (PMID:25728920; PP4_strong). In silico tools predict a deleterious effect on gene product ( REVEL score = 0.953; PP3). This variant is seen in triple heterozygosity with two other variants, one of which (p.Ser237CysfsTer13) has been classified as Pathogenic by the ClinGen Platelet VCEP (PM3_supporting). This variant meets GT specific criteria PM2_Supporting,PP4_Strong, PP3 and PM3_Supporting and is therefore classified as likely pathogenic.

PP4_Strong

PMID:25728920 reports an individual GT3 with significant mucocutaneous bleeding (Epistaxis, ecchymoses, purpura since birth, GI bleeding, excessive menstrual bleeding), platelet aggregation was absent with three physiological agonists(normal with ristocetin) and flow cytometry demonstrated <5% αIIbβ3 surface expression.Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions (UTR).

PM3_Supporting

p.Leu118His has been reported in triple heterozygosity with two other variants, one a missense variant p.Asp578Asn and the other a frameshift variant p.Ser237CysfsTer13. The p.Asp578Asn and p.Ser237CysfsTer13 variants have be confirmed to be in cis (occurring on the same allele) by sequencing and HRM analysis of the patient's daughter. However, no information about the phase of this particular variant is available. (PMID: 25728920.) The p.Ser237CysfsTer13 has been classified as Pathogenic by ClinGen Platelet VCEP. Since this variant, p.Leu118His, occurs with a Pathogenic variant (phase unconfirmed), PM3_Supporting criteria is met as per GT rule specifications (0.5 points).

PM2_Supporting

Absent from gnomAD, ExAC and 1000 Genomes.

PP3

REVEL score = 0.953 which is above the impact threshold of 0.70

PS3

PMID : 25728920 analysed transfected COS7 cells for expression of cell surface αIIbβ3 by flowcytometry. They reported a loss of αIIbβ3 expression with molecular modeling predicting changes in H-bonding. However no information on the level of reduced expression is available.

Approved on: 2023-10-17

Published on: 2023-10-17

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