ClinVar Miner

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

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Total submissions: 3
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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 2019-02-18 criteria provided, single submitter clinical testing Variant summary: HBB c.2T>A (p.Met1Lys) 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. Missense mutation of the initiation codon is widely regarded as deleterious (p.Met1Val, p.Met1Thr, and p.Met1Arg are internally classified as pathogenic). 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. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245874 control chromosomes (gnomAD). c.2T>A has been reported in the literature in heterozygous state (once as a de novo occurrence), in 3 individuals, at least two of them presenting with beta-thalassemia intermedia (Vasseur_2017, Lacan_2005, Waye_1997). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985744 SCV001134221 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The variant disrupts the natural start codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000588257 SCV001244629 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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