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

gnomAD frequency: 0.00005  dbSNP: rs33978907

Total submissions: 10

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	RCV000506540	SCV000603914	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	The HBB c.*110T>C variant (rs33978907, HbVar ID: 968), 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: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Italia K et al. Variable haematological and clinical presentation of beta-thalassaemia carriers and homozygotes with the Poly A (T?C) mutation in the Indian population. Eur J Haematol. 2012; 89(2):160-4. PMID: 22690826. 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. PMID: 4018033. Sinha S et al. Profiling beta-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. PMID: 21119755. Sivalingam M et al. Molecular study and genotype/phenotype correlation of beta thalassemia in Malaysia. Int J Lab Hematol. 2012 Aug;34(4):377-82. PMID: 22335963.
Invitae	RCV000506540	SCV000946427	pathogenic	not provided	2023-12-12	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. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of multiple amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs33978907, gnomAD 0.03%). This variant has been observed in individuals with beta-thalassemia (PMID: 1787101, 4018033, 22335963, 22690826, 23590658). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36332). Studies have shown that this variant results in the activation of a cryptic splice site in 3' UTR (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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000506540	SCV003929400	pathogenic	not provided	2021-06-11	criteria provided, single submitter	clinical testing
OMIM	RCV000016730	SCV000037000	pathogenic	Beta-plus-thalassemia	1985-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000445649	SCV000537300	not provided	beta Thalassemia		no assertion provided	literature only
Counsyl	RCV000445649	SCV001132413	pathogenic	beta Thalassemia	2015-11-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000445649	SCV002089181	pathogenic	beta Thalassemia	2020-10-06	no assertion criteria provided	clinical testing