Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812582 | SCV002049707 | pathogenic | not provided | 2023-08-21 | criteria provided, single submitter | clinical testing | The codon 108 (-C) (HBA1: c.328delC; p. Leu110TrpfsTer24, also known as p.Leu109fs when numbered from the mature protein, rs281864535, HbVar ID: 2724) is reported in the literature in the heterozygous state in individuals with hematological findings consistent with alpha-thalassemia silent carrier status (Henderson 2016, Oron-Karni 2000), and in an individual affected with HbH disease who carried a different variant on the opposite chromosome (Gilad 2017). This variant is reported in HbVar (see link), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the HBA1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 24 amino acid residues not usually present. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Gilad O et al. Molecular diagnosis of a-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562. PMID: 28160324 Henderson SJ et al. Ten Years of Routine a- and ß-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations. Hemoglobin. 2016;40(2):75-84. PMID: 26635043 Oron-Karni V et al. Diversity of alpha-globin mutations and clinical presentation of alpha-thalassemia in Israel. Am J Hematol. 2000 Nov;65(3):196-203. PMID: 11074535 |
| 3billion, |
RCV002250774 | SCV002521321 | likely pathogenic | alpha Thalassemia | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to be associated with HBA1 related disorder (ClinVar ID: VCV001331033 / PMID: 11074535). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Fulgent Genetics, |
RCV002482328 | SCV002781212 | pathogenic | Heinz body anemia; alpha Thalassemia; Hemoglobin H disease; Methemoglobinemia, alpha type; Erythrocytosis, familial, 7 | 2022-05-17 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV002250774 | SCV004848825 | pathogenic | alpha Thalassemia | 2022-11-03 | criteria provided, single submitter | clinical testing | The p.Leu110TrpfsX24 variant in HBA1--also known as Hb Sciacca and (α1 cod109 (−C))-- has been reported in the heterozygous state in individuals with hematological findings consistent with alpha-thalassemia silent and in the compound heterozygous state in at least 1 individuas with anemia and microcytosis (Henderson 2016 Oron-Karni 2000 PMID: 11074535, Gilad 2017 PMID: 28160324, Keikhaei 2018 PMID: 29627922, Cardiero 2021 PMID: 34680508, HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2724 ). This variant has been reported in ClinVar (Variation ID: 1331033) and was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 110 and leads to a premature termination codon 24 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies support an impact on protein function (Cardiero 2021 PMID: 34680508). Loss of function of the HBA1 gene is an established disease mechanism in autosomal recessive alpha Thalassaemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PVS1_Strong, PM2_supporting, PS3_Supporting, PM3. |