ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.*110T>C (rs33978907)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506540 SCV000601229 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999917 SCV000603914 pathogenic none provided 2020-04-02 criteria provided, single submitter clinical testing The HBB c.*110T>C variant (rs33978907), also known as Poly A (T->C), has been reported in multiple patients diagnosed with beta thalassemia, and has been found in a homozygous state, or in-trans with other pathogenic variants (Hoppe 2013, Italia 2012, Orkin 1985, Sinha 2009, Sivalingam 2012, see link to HbVar). Functional characterization of the variant indicates the loss of the canonical polyadenylation site, resulting in an elongated HBB transcript that is less efficiently processed by a downstream cryptic polyadenylation site (Orkin 1985). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 36332), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the 3' UTR, and computational algorithms (Poly A miner) predict an impact on the transcript, consistent with observations from the functional study. Based on available information, the c.*110T>C variant is considered to be pathogenic. References: Link to HbVar database for Poly A (T -> C): Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. Italia K et al. Variable haematological and clinical presentation of ß-thalassaemia carriers and homozygotes with the Poly A (T?C) mutation in the Indian population. Eur J Haematol. 2012; 89(2):160-4. Orkin S et al. Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. EMBO J. 1985; 4(2):453-6. Sinha S et al. Profiling ß-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. Hugo J. 2009 Dec;3(1-4):51-62 Sivalingam M et al. Molecular study and genotype/phenotype correlation of ß Thalassemia in Malaysia. Int J Lab Hematol. 2012 Aug;34(4):377-82.
Invitae RCV000506540 SCV000946427 pathogenic not provided 2020-03-29 criteria provided, single submitter clinical testing This sequence change falls in the 3'UTR of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant has been observed in several individuals affected with beta-thalassemia (PMID: 1787101, 4018033, 22690826, 22335963, 23590658). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36332). Experimental studies have shown that this sequence change disrupts the recognition signal for normal endonucleolytic cleavage and polyadenylation of mRNA transcripts and results in an elongated RNA molecule (PMID: 4018033). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004557 SCV001163639 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000445649 SCV001338948 pathogenic beta Thalassemia 2020-03-05 criteria provided, single submitter clinical testing Variant summary: HBB c.*110T>C is located in the 3UTR downstream of the termination codon involves the alteration of a conserved nucleotide. The variant of interest is located within the known "polyA' tail, thus expected to alter mRNA expression, which is supported by Orkin_1985 functional findings. The variant allele was found at a frequency of 6.4e-05 in 31396 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.011). c.*110T>C has been reported in the literature in multiple individuals affected with Beta Thalassemia and implicated to be the third most common allele in India (Orkin_1985, Sinha_2009, Italia_2012). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000016730 SCV000037000 pathogenic Beta-plus-thalassemia 1985-02-01 no assertion criteria provided literature only
GeneReviews RCV000445649 SCV000537300 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Counsyl RCV000445649 SCV001132413 pathogenic beta Thalassemia 2015-11-16 no assertion criteria provided clinical testing

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