Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759054 | SCV000888135 | pathogenic | not provided | 2024-02-09 | criteria provided, single submitter | clinical testing | The c.427T>G (p.*143Gluext*31) pathogenic variant leads to the replacement of the normal stop codon by a glutamic acid and extension of the alpha-globin chain by 31 amino acids (p.*143Gluext*31). Individuals positive for this variant and the -alpha3.7 deletion have a clinical presentation that is comparable to that of mild Hb H disease (see Hb Var (http://globin.cse.psu.edu/cgi-bin/hbvar/counter) and PMID: 9255612 (1997)). Based on the available information, this variant is classified as pathogenic. |
| Labcorp Genetics |
RCV000759054 | SCV001210808 | likely pathogenic | not provided | 2023-08-07 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 15653). This variant is also known as Hb Seal Rock. This protein extension has been observed in individual(s) with thalassemia (PMID: 9255612). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs41464951, gnomAD 0.01%). This sequence change disrupts the translational stop signal of the HBA2 mRNA. It is expected to extend the length of the HBA2 protein by 31 additional amino acid residues. This variant results in an extension of the HBA2 protein. Other variant(s) that result in a similarly extended protein product (p.*143Glnext*31) have been determined to be pathogenic (PMID: 2298455, 4944483, 6725554, 9057661, 12393486, 20507641). This suggests that these extensions are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| ARUP Laboratories, |
RCV000759054 | SCV001472431 | pathogenic | not provided | 2021-08-05 | criteria provided, single submitter | clinical testing | The Hb Seal Rock variant (HBA2: c.427T>G; p.Ter143Glu, also known as Ter142Glu when numbered from the mature protein, rs41464951) is described in the literature in individuals with HbH disease who carry alpha globin deletions on the opposite chromosome (Das 2014, Merritt 1997, see HbVar link). This variant is reported in ClinVar (Variation ID: 15653), and found in the general population with a low overall allele frequency of 0.003% (1/30200 alleles) in the Genome Aggregation Database. This variant abolishes the canonical termination codon, resulting in an elongated protein that is unstable, similar to other stop loss variants (Hb Constant Spring, Hb Icaria)(see HbVar links and references therein). Based on available information, the Hb Seal Rock variant is considered to be pathogenic. References: Link to HbVar database for Hb Constant Spring: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=703&.cgifields=histD Link to HbVar database for Hb Icaria: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=704&.cgifields=histD Link to HbVar database for Hb Seal Rock: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=706&.cgifields=histD Das R et al. Wide Spectrum of Molecular and Clinical Heterogeneity in HbH Disease in North Indian Patients. Blood 124.21 (2014): 1358. Web. 21 Aug. 2018. Merritt D et al. Hb Seal Rock ((alpha 2)142 term-->Glu, codon 142 TAA-->GAA): an extended alpha chain variant associated with anemia, microcytosis, and alpha-thalassemia-2 (-3.7 Kb). Hemoglobin. 1997 Jul;21(4):331-44. |
| OMIM | RCV000016939 | SCV000037211 | other | HEMOGLOBIN SEAL ROCK | 2018-05-22 | no assertion criteria provided | literature only | |
| Natera, |
RCV001275682 | SCV001461042 | likely pathogenic | alpha Thalassemia | 2020-09-16 | no assertion criteria provided | clinical testing |