Evidence Repository - Clinical Genome Resources

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Variant: NM_000419.5:c.2602-3C>A

CA8602635

996161 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9cce91bd-091f-4606-9c88-f313736a333c

Approved on: 2023-09-07

Published on: 2023-09-21

HGVS expressions

NM_000419.5:c.2602-3C>A

NC_000017.11:g.44375719G>T

CM000679.2:g.44375719G>T

NC_000017.10:g.42453087G>T

CM000679.1:g.42453087G>T

NC_000017.9:g.39808613G>T

NG_008331.1:g.18787C>A

ENST00000262407.6:c.2602-3C>A

ENST00000648408.1:c.2033-3C>A

ENST00000262407.5:c.2602-3C>A

ENST00000587295.5:c.253+114C>A

ENST00000592462.5:n.1397-3C>A

NM_000419.3:c.2602-3C>A

NM_000419.4:c.2602-3C>A

NM_000419.5(ITGA2B):c.2602-3C>A

Uncertain Significance

PM2_Supporting PP4_Strong

BP7 BP2 PM3

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

The NM_000419.4:c.2602-3C>A is a splice region variant in intron 25. The variant occurs at a very low frequency in population databases, with 0.00003830 (1/26801 alleles) in the gnomADv2.1.1 Latino/Admixed American population (PM2_supporting). It is reported in one compound heterozygous individual with the c.2602-2A>G and Thr281Ile (PMID: 25373348). GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced (PP4_strong). In summary, there is insufficient evidence at this time to classify this variant for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_Supporting, PP4_Strong.

PM2_Supporting

This variant is at an extremely low frequency (below the <1/10,000 threshold) with an overall allele frequency from gnomAD of 0.000005515 and MAF of 0.00003830 (1/26801 alleles) in the Latino population.

PP4_Strong

GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced.

BP7

HSF and MaxEntScan do not predict a significant impact on splicing however the cytosine at position 3 has been reported to be essential, as the c.2602-3C>G mutation causes in-frame exon 26 skipping.

BP2

In PMID: 25373348 c.2602-2A>G (classified likely pathogenic by the PD-EP) was reported as occurring "together with" c.2602-3C>A, however the cis/trans relationship was not confirmed.

PM3

Patient GT16 of PMID: 25373348 is compound heterozygous for c.2602-2A>G/c.2602-3C>A and Thr281Ile (classified likely pathogenic by the Platelet Disorders VCEP). Phase was not confirmed.

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