ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.-140C>G (rs34999973)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589253 SCV000697079 uncertain significance not specified 2019-03-18 criteria provided, single submitter clinical testing Variant summary: HBB c.-140C>G variant leads to a substitution in the 5' UTR conserved promoter sequence (CACCC box) at a conserved nucleotide. The transcription factor erythroid Kruppel-like factor (EKLF) specifically activates the b-globin gene by interacting with the proximal b-globin CACCC box, a known hot spot for thalassaemia mutations. It has been shown that EKLF requires both the proximal and distal CACCC boxes to maximally stimulate the b-globin gene, and thus changes to the CACCC boxes are expected to reduce HBB expression (PMID:15384985). 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 30974 control chromosomes (gnomAD). c.-140C>G has been reported in the literature in 4 heterozygous carrier members of a family, with the proband being reported with anemia, microcytosis, hypochromia and elevated HbA2 (Rizo-de-la-Torre_2017). The variant is reported in the Ithanet database as "globin gene causative mutation". Another substitution at the same position, c.-140C>T has been classified as a pathogenic variant by our laboratory and it is reported to impair mRNA synthesis (PMIDs: 3457470 and 14555318). Furthermore, other substitutions in the same CACCC box have been classified as pathogenic by our laboratory (e.g. c.-138C>T, c.-138C>A, c.-137C>G, c.-137C>T, c.-136C>G). 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 VUS-possibly pathogenic.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV001078396 SCV001244601 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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