ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.2T>G (p.Met1Arg) (rs33941849)

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Total submissions: 7
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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 2017-07-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507488 SCV000603920 pathogenic not specified 2016-10-01 criteria provided, single submitter clinical testing
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
Integrated 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.
OMIM RCV000016691 SCV000036961 pathogenic beta^0^ 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

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