Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000505904 | SCV000601269 | pathogenic | not provided | 2021-10-06 | criteria provided, single submitter | clinical testing | This variant disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is associated with beta-zero-thalassemia and is known to be a common Chinese beta-thalassemia pathogenic variant (PMID: 2306523 (1990), 27829298 (2016), 34474730 (2021), 34293487 (2021)). Based on the available information, this variant is classified as pathogenic. |
ARUP Laboratories, |
RCV000505904 | SCV000603920 | pathogenic | not provided | 2019-12-19 | criteria provided, single submitter | clinical testing | The HBB c.2T>G; p.Met1? variant (rs33941849) is reported in the literature in individuals affected with beta(0) thalassemia (HbVar database), with no detectable expression of the beta globin protein in a patient possessing a beta(0) thalassemia variant on the other chromosome (Lam 1990). This variant is reported in ClinVar (Variation ID: 15434), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant ablates the canonical translation initiation codon, and is predicted to lead to an aberrant or absent protein. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.2T>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=777 Lam V et al. A new single nucleotide change at the initiation codon (ATG----AGG) identified in amplified genomic DNA of a Chinese beta-thalassemic patient. Blood. 1990 75(5):1207-8. |
Counsyl | RCV000664667 | SCV000788668 | pathogenic | beta Thalassemia | 2017-10-05 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001004361 | SCV001163299 | pathogenic | Hb SS disease | criteria provided, single submitter | clinical testing | ||
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000664667 | SCV001363914 | pathogenic | beta Thalassemia | 2020-07-14 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.2T>G (p.Met1Arg) 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. Arginine is not a known alternative start codon for eukaryotes in nature; thus, translation would be predicted to start at the next Met in the HBB protein (which is at amino acid 56), causing a loss of translation of the normal N-terminus of the protein. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). c.2T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia (e.g. Lam_1990, Lee_2002, Su_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This codon is in a mutational hotspot where other changes [such as: p.M1I (c.3G>A, C, and T), p.M1L, p.M1K, p.M1T and p.M1V] at the same residue have also been found in HBB patients (source: HGMD). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV000505904 | SCV003439604 | pathogenic | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56. Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive beta thalassemia (PMID: 12955718, 14715623, 29695942). This variant has been reported in individual(s) with autosomal dominant beta thalassemia (PMID: 8144357); however, the role of the variant in this condition is currently unclear. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 15434). This variant is also known as CD0T>G, Initiation codon ATG‚ÜíAGG. |
OMIM | RCV000016691 | SCV000036961 | pathogenic | Beta zero thalassemia | 1992-06-01 | no assertion criteria provided | literature only | |
The ITHANET community portal, |
RCV000664667 | SCV001244631 | pathogenic | beta Thalassemia | 2019-11-25 | no assertion criteria provided | curation | |
Natera, |
RCV000664667 | SCV002091622 | pathogenic | beta Thalassemia | 2017-03-17 | no assertion criteria provided | clinical testing |