ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-50A>C (rs34305195)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029957 SCV000052612 pathogenic beta Thalassemia 2017-02-08 criteria provided, single submitter clinical testing Variant summary: The HBB c.-50A>C (also known as CAP +1 A>C) variant involves the alteration of a non-conserved nucleotide, which lies in the CAP-site from where transcription starts. One in silico tool predicts a damaging outcome for this variant. This variant was found in 12/119792 control chromosomes at a frequency of 0.0001002, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). The variant was reported in numerous Beta Thalassemia patients individuals in the literature. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508619 SCV000605834 pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing
Invitae RCV000508619 SCV000937271 likely pathogenic not provided 2018-12-24 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. This variant is present in population databases (rs34305195, ExAC 0.07%). This variant has been observed in individuals affected with beta thalassemia (PMID: 19254853, 22335963, 27263053). It is also known as the "Cap+1" or "Cap site+1" variant in the literature. ClinVar contains an entry for this variant (Variation ID: 36292). Experimental studies have shown that this non-coding change causes a reduction in HBB mRNA expression (PMID: 3683554). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001389 SCV001158594 pathogenic not specified 2019-03-06 criteria provided, single submitter clinical testing The HBB c.-50A>C variant (rs33915217), also known as CAP +1 (A>C), is reported in the literature in the homozygous state in individuals affected with beta thalassemia, and in the compound heterozygous state in individuals with varying clinical presentations (Garewal 2007, Khattak 2012, Wong 1987, HbVar database). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 36292), and is found in the South Asian population with an allele frequency of 0.085% (26/30,504 alleles) in the Genome Aggregation Database. This variant occurs in the 5' untranslated region at a nucleotide that is moderately conserved. Although the exact molecular mechanism causing pathogenicity is unknown (Thein 2013), the c.-50A>C variant is considered to be pathogenic. References: Link to HbVar for CAP+1 (A>C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=770&.cgifields=histD Garewal G et al. The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. Eur J Haematol. 2007 Nov;79(5):417-21. Khattak SA et al. Prevalence of various mutations in beta thalassaemia and its association with haematological parameters. J Pak Med Assoc. 2012 Jan;62(1):40-3. Thein SL. The molecular basis of B-thalassemia. Cold Spring Harb Perspect Med. 2013 May 1;3(5):a011700. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6.
GeneReviews RCV000029957 SCV000537293 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Counsyl RCV000029957 SCV001132218 pathogenic beta Thalassemia 2016-02-10 no assertion criteria provided clinical testing

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