ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-78A>C (rs33931746)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000589656 SCV000790517 pathogenic beta Thalassemia 2017-03-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589656 SCV000697148 pathogenic beta Thalassemia 2017-03-10 criteria provided, single submitter clinical testing Variant summary: The HBB c.-78A>C variant involves the alteration of a non-conserved nucleotide in the promoter region (transcriptional TATA box). One in silico tool predicts a damaging outcome for this variant. The variant of interest was observed in controls with an allele frequency of 0.0000322 (1/31018), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in multiple BTHAL-ITMD cases both as homozygotes and compound heterozygotes. In addition, multiple reputable databases classified this variant as pathogenic. Furthermore, another variant at this location, c.-78A>G has been reported and classified by LCA as "pathogenic," supporting the importance of this region/location for proper function. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Pathogenic."
Invitae RCV000508592 SCV000944281 pathogenic not provided 2018-09-05 criteria provided, single submitter clinical testing This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed to be homozygous or on the opposite chromosome (in trans) from several other pathogenic variants in individuals affected with HBB-related disease (PMID: 2200760, 8619407, 17994378, 19960060, 16103715). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In the literature, this variant is also known as -28 A>C. ClinVar contains an entry for this variant (Variation ID: 15470). Experimental studies have shown that this promoter variant results in decreased binding of the TATA-binding protein and decreased transcription of the HBB mRNA (PMID: 2987224, 24616209). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016728 SCV000036998 pathogenic Beta-plus-thalassemia 1982-06-10 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508592 SCV000605839 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing

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