Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001811159 | SCV000603946 | uncertain significance | not provided | 2023-11-28 | criteria provided, single submitter | clinical testing | The Hb N-Seattle (HBB: c.184A>G; p.Lys62Glu, also known as Lys61Glu when numbered from the mature protein, rs33995148, HbVar: 353) has been reported in a heterozygous blood donor with normal clinical presentation. However, its phenotype when found with other pathogenic globin variants is uncertain, and has not been described in the literature. The Hb N-Seattle hemoglobin variant is stable, and comprises half of the total hemoglobin in the individual (HbVar database and references therein). It is listed in ClinVar (Variation ID: 15280), but absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.699). Although Hb N-Seattle has not been associated with clinical symptoms or hemoglobin abnormalities, there is insufficient information to determine its clinical significance with certainty. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004525854 | SCV005040197 | uncertain significance | not specified | 2024-03-05 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.184A>G (p.Lys62Glu, also known as Lys61Glu, Hb N-Seattle) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.184A>G has been reported in the literature in individuals affected with Anemia but also found in individuals without clinical symptoms (example, Jones_1968, Schroeder_1982). These report(s) do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. At least one publication reports experimental evidence evaluating an impact on protein function using blood samples from a heterozygous donor without clinical presentation, however, does not allow convincing conclusions about the variant effect (Jones_1968). The following publications have been ascertained in the context of this evaluation (PMID: 5637049, 7092797). ClinVar contains an entry for this variant (Variation ID: 15280). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| OMIM | RCV000016510 | SCV000036778 | other | HEMOGLOBIN N (SEATTLE) | 2017-12-12 | no assertion criteria provided | literature only | |
| Natera, |
RCV001826466 | SCV002089216 | uncertain significance | beta Thalassemia | 2020-03-31 | no assertion criteria provided | clinical testing |