Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001811644 | SCV001477752 | pathogenic | not provided | 2019-08-15 | criteria provided, single submitter | clinical testing | The HBB c.1A>C; p.Met1? variant is reported in the literature in an individual affected with microcytic anemia and diagnosed as a beta-thalassemia carrier (Knott 2006). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical translation initiation codon and is predicted to result in an aberrant or absent protein. Other variants that affect the HBB initiation codon have been reported in individuals with beta-thalassemia or microcytic anemia and are considered pathogenic (HbVar database and references therein). Based on available information, the c.1A>C variant is considered to be pathogenic. References: Link to HbVar database: http://globin.bx.psu.edu/ Knott M et al. Novel and Mediterranean beta thalassemia mutations in the indigenous Northern Ireland population. Blood Cells Mol Dis. 2006 Mar-Apr;36(2):265-8. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001078260 | SCV003929039 | likely pathogenic | beta Thalassemia | 2023-04-12 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.1A>C (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next available downstream ATG codon, located at codons 21-22, would result in a frameshift leading to premature termination of translation at codons 60-61, likely resulting in a missing/non-functional protein product (Knott_2006). Alternatively, activation of the next downstream in-frame start codon (Met56) would result in a shortened protein missing the first 55 amino acids from the protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). c.1A>C has been reported in the literature in the heterozygous state in at least two individuals presenting with beta-thalassemia minor/intermedia (e.g. Knott_2006, Rizo_2021). Thus, it is expected that in homozygosity and/or compound heterozygosity, this variant is likely to cause BTHAL MJR phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, missense mutation of the initiation codon is widely regarded as deleterious (p.Met1Val, p.Met1Thr, p.Met1Ile, and p.Met1Arg are internally classified as pathogenic). Thus, in the HBB gene, other changes in the initiation codon are expected to cause severe BTHAL disease. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| The ITHANET community portal, |
RCV001078260 | SCV001244403 | pathogenic | beta Thalassemia | 2019-11-25 | no assertion criteria provided | curation |