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_000419.4(ITGA2B):c.1946+1G>A

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CA8602901

569057 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a42a7514-27fb-48ef-95e7-ff2157e7ba75

Approved on: 2020-09-06

Published on: 2021-01-28

HGVS expressions

NM_000419.4:c.1946+1G>A

NM_000419.4(ITGA2B):c.1946+1G>A

NC_000017.11:g.44378642C>T

CM000679.2:g.44378642C>T

NC_000017.10:g.42456010C>T

CM000679.1:g.42456010C>T

NC_000017.9:g.39811536C>T

NG_008331.1:g.15864G>A

NM_000419.3:c.1946+1G>A

NM_000419.5:c.1946+1G>A

ENST00000262407.5:c.1946+1G>A

ENST00000592462.5:n.741+1G>A

Pathogenic

PP4_Moderate PVS1 PM2_Supporting

PM3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The splicing variant, c.1946+1G>A, has been observed in at least one compound heterozygous patient in the literature with a phenotype highly specific to GT (PMID: 15099289). The canonical IVS19+1 donor splice site is lost, which is expected to result in skipping of exon 19 causing a reading frame shift with 10 new amino acids followed by a stop codon that leads to NMD. The variant is absent form ExAC, gnomAD, and 1000 Genomes. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PP4_Moderate.

PP4_Moderate

One proband has been described in PMID: 15099289 with a phenotype highly specific to GT; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3.

Patient J.V. has history of severe bruising and epistaxis with a normal to mildly elevated platelet count of (430–660×10^9 L−1). There is no aggregation in response to ADP, epinephrine or arachidonic acid, but a small residual response to collagen on two occasions. Ristocetin‐induced agglutination was low‐normal. Flow cytometry found an approximate 4% residual αIIbβ3 surface expression and Western blot analysis confirmed the presence of small amounts of residual αIIb heavy chain (αIIbH) and β3 in the patient's platelets. The patient was also diagnosed with type 1 VWD. PubMed:15099289

PVS1

The donor site of intron 19 was disrupted which is expected to result in skipping of exon 19 causing a reading frame shift with 10 new amino acids followed by a stop codon that leads to NMD.

PM2_Supporting

The variant is found at an extremely low frequency (below the <1/10,000 threshold); the overall allele frequency on gnomAD is 0.000005690 with a MAF of 0.00007555 (1/13,236 alleles) in the East Asian population.

PM3

The proband was described to have triple heterozygosity with this maternally inherited splice variant in trans with both Val982Met and Ala958Thr (Likely Benign), however it was asserted that Ala989Thr was a polymorphism and Val982Met is the second variant of interest in this patient. However, to avoid circularity the proband was counted only towards the classification of Val982Met not c.1946+1G>A. PubMed:15099289

Curation History

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