ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.2T>A (p.Met1Lys) (rs33941849)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588257 SCV000697104 likely pathogenic beta Thalassemia 2017-06-26 criteria provided, single submitter clinical testing Variant summary: HBB c.2T>A affects a conserved nucleotide, resulting in a predicted amino acid change p.Met1Lys. However this Met residue is the initiation codon of HBB, and missense mutation of the initiation codon is widely regarded as deleterious (p.Met1Val, p.Met1Thr, and p.Met1Arg are classified as pathogenic by LCA). In the HBB gene, other changes at this codon are pathogenic and mutations in the initiation codon are expected to cause severe BTHAL disease. The nearest downstream ATG is codon 55. It is possible that translation of the mutant mRNA initiates from the single in-frame initiation codon (codon 55) and produces a truncated beta-chain that is highly unstable. 4/4 in-silico tools predict this variant to be damaging, however functional studies have not been carried out. This variant was not found in approximately 121232 control chromosomes from ExAC. The variant has been reported in heterozygous state, once as a de novo occurrence, in 2 individuals whom presented with hematologic profile of beta-thalassemia intermedia. Thus, it is expected that in homozygosity and/or compound heterozygosity, this variant is likely to cause BTHAL MJR phenotype. Taken together, this is probably a disease variant has currently been classified as likely pathogenic.

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