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_000212.3(ITGB3):c.55del (p.Ala19fs)

Curation Version - 1.0
Curation History
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CA626377544

1438062 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7fdd5fd0-80ed-4c6f-b3f7-adbd891c8ae7

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000212.3:c.55del

NM_000212.3(ITGB3):c.55del (p.Ala19fs)

NC_000017.11:g.47253916del

CM000679.2:g.47253916del

NC_000017.10:g.45331282del

CM000679.1:g.45331282del

NC_000017.9:g.42686281del

NG_008332.2:g.5075del

ENST00000696963.1:c.55del

ENST00000559488.7:c.55del

ENST00000559488.5:c.55del

ENST00000560629.1:c.20del

ENST00000571680.1:c.55del

NM_000212.2:c.55del

Uncertain Significance

PM2_Supporting PVS1_Moderate

PP4

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.55del variant in ITGB3 is a deletion of 1 nucleotide in exon 1, resulting in a shift of the reading frame and a premature stop signal (p.Ala19Argfs*7). Premature termination codon within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_moderate. This variant occurs at a very low allele frequency overall in gnomAD v4.0.0 of 0.000006374 with a MAF of 0.000002980 (3/1006570) in the non-Finnish European population (PM2_Supporting). The variant has been reported heterozygous in one individual (PMID: 31980526) but has not been reported in any patients with a Glanzmann thrombasthenia phenotype. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate, PM2_Supporting.

PM2_Supporting

This variant occurs at a very low allele frequency overall in gnomAD v4.0.0 of 0.000006374 with a MAF of 0.000002980 (3/1006570) in the non-Finnish European population which is below the the <0.0001 threshold for PM2_supporting.

PVS1_Moderate

The c.55del (p.Ala19ArgfsTer7) variant in exon 1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/15. Premature termination codon within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_moderate.

PP4

The variant has been reported heterozygous in one individual (PMID: 31980526) who does not have a Glanzmann thrombasthenia phenotype.

Curation History

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