Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000506874 | SCV000601304 | pathogenic | not provided | 2017-06-13 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001375559 | SCV001572438 | likely pathogenic | Hemoglobinopathy | 2021-04-01 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.440_441dupAC (p.X148ThrfsX12, also known as Hb Tak in the literature) causes a frameshift which results in an extension of the protein. The variant was absent in 251368 control chromosomes. c.440_441dupAC has been reported in the literature in homozygosity or compound heterozygosity with other pathogenic variants in individuals affected with Hemoglobinopathies, including polycythemia (e.g. Hoyer_1998, Tanphaichitr_2003). In some individuals, abnormal hemoglobin was detected by HPLC, however clinical symptoms were either mild or not reported (e.g.Flatz_1971, Jindadamrongwech_2010). The variant was also identified in an individual diagnosed with erythrocytosis whom was reported to carry this variant in compound heterozygosity with HbE, however, the proband's father with the identical genotype was not reported to have any clinical symptoms of disease, suggesting reduced penetrance (e.g. Teawtrakul_2010). Hb Tak has also recently been reported in a patient who also carried Hb Constant Spring (HbCS) and was affected with a severe form of hemolytic anemia (Choed-Amphai_2020). Several publications report experimental evidence indicating that cells with the variant have increased affinity for oxygen (e.g. Imai_2001, Tanphaichitr_2003). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV000506874 | SCV003441573 | uncertain significance | not provided | 2022-09-13 | criteria provided, single submitter | clinical testing | This sequence change results in a frameshift in the HBB gene (p.*148Thrext*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the natural stop codon of the HBB protein and extend the protein by 11 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with mild polycythemia, secondary erythrocytosis (PMID: 604313, 9494047, 12621249, 15768557, 20353353). This variant is also known as Hb Tak, HBB:c.441_442insAC. ClinVar contains an entry for this variant (Variation ID: 439161). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| 3billion | RCV003313962 | SCV004013693 | likely pathogenic | Beta-thalassemia HBB/LCRB | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through altering the stop codon, which leads to elongate the protein length. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000439161 / PMID: 9494047). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. | |
| OMIM | RCV000016621 | SCV000036890 | other | HEMOGLOBIN TAK | 2017-12-12 | no assertion criteria provided | literature only |