ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.-77_-76delAA (rs63750953)

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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 RCV000587966 SCV000697147 likely pathogenic beta Thalassemia 2016-12-26 criteria provided, single submitter clinical testing Variant summary: The HBB c.-77_-76delAA variant, also known as -27(-AA), is present within ATAA box which is known to be involved in transcription. This not only changes the sequence of the ATAA box from ATAAAA to ATAAGT, but also alters the distance between the ATAA box and the normal transcription start sequence. Both the sequence of the ATAA box and the spacing relative to the transcription start site are thought to be important determinants of tissue-specific expression of mammalian genes (Eng_2007). Mutation Taster predicts a damaging outcome for this variant. Mutations in ATAA box are established to cause BTHAL ITMD there are several mutations in the box such as c.-140C>T, c.-138C>A, c.-138C>T, c.-137C>A, c.-137C>T,-137C>G, c.-136C>T and c.-136C>G. This variant of interest is absent in 119754 control chromosomes from ExAC. This variant has been reported in two subjects in literature; one is neonate who showed FSA (Hb S/b+-thalassemia) profile on NBS (Eng_2007) and another is an 8-yr-old patient with mild BTHAL ITMD who was compound heterozygous for this variant and other ITMD-causing mutation c.-138C>T (Basran_2008). In the latter patient, two unaffected family members with BTHAL trait were carrier for the variant. Reputable databases have classified it as pathogenic/likely pathogenic. Taken together, this variant is classified as likely pathogenic.

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