ClinVar Miner

Submissions for variant NM_002049.4(GATA1):c.886A>C (p.Thr296Pro)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz RCV003325446 SCV004031421 pathogenic Thrombocytopenia, X-linked, with or without dyserythropoietic anemia 2023-09-04 criteria provided, single submitter clinical testing We identified this variant in 3 individuals from one family (PMID: 36231035). The index patient is hemizygous for this variant, his daughter and mother heterozygous. The index patient and his daughter suffer from hematoma and frequent epistaxis (ISTH BAT score index = 9; Daughter = 5) and presented with macrothrombocytes. Additionally, the index had thrombocytopenia, however the daughter had no thrombocytopenia but mild spherocytosis and hemolysis. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry) in the index and affected daughter. In addition, both presented with mild dyserythropoiesis (Lu(a-b-); high HbF), which was altered in the daughter by the missense variant NM_000342.4(SLC4A1): c.2210C>T, resulting in a mild spherocytic phenotype. We were able to prove that the affected daughter had skewed X inactivation in favor of the affected allele (~86% activity). It was not possible to examine the variant-bearing but apparently healthy mother of the index case, but we suspect random X inactivation. The variant is highly conserved, rare as it is not known in dbSNP, and prediction tools (Mutation Taster, PolyPhen2, SIFT, PROVEAN) all predict pathogenicity. It is located between the C-terminal zinc finger and the nuclear localization sequence of GATA1. In this region (aa283–300), no common variants (MAF > 1%) and only two pathogenic variants also causing XLT with mild anemia have been reported (PMID: 27342114, 36291092, 35446378). Therfore, we classified this variant as pathogenic.

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. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.