ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.2T>G (p.Met1Arg)

dbSNP: rs33941849
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Total submissions: 9
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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, Molecular Genetics and Genomics, 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, LabCorp 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, The Cyprus Institute of Neurology and Genetics RCV000664667 SCV001244631 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation
Natera, Inc. RCV000664667 SCV002091622 pathogenic beta Thalassemia 2017-03-17 no assertion criteria provided clinical testing

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