ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.92+6T>C (rs35724775)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417932 SCV000513211 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing The c.92+6T>C variant in the HBB gene has been reported previously using alternate nomenclature (IVS1-6T>C) in the homozygous state or with another HBB variant in multiple individuals with beta-thalessemia (Ulasli et al., 2015; Silva et al., 2016). This variant reduces the quality of the splice donor site in intron 1. Transgenic mice homozygous for the c.92+6T>C variant exhibit aberrantly spliced mRNA’s (Breveglieri et al., 2015). The c.92+6T>C variant is observed in 17/66,726 (0.025%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). We interpret c.92+6T>C as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507521 SCV000603894 pathogenic not specified 2018-07-05 criteria provided, single submitter clinical testing The HBB c.92+6T>C variant (also known as IVS-I-6 T->C) has been reported in multiple individuals with beta thalassemia (Orkin 1982, Efremov 1994, HbVar database and references therein). Functional characterization of the variant indicates aberrant splicing of the first and second exons of HBB, leading to production of non-functional beta globin mRNA and reduction of wildtype transcripts (Breveglieri 2015). The variant is listed in the dbSNP variant database (rs35724775), and observed in the Exome Aggregation Consortium general population database at a frequency of 0.015 percent. Computational algorithms (GeneSplicer, Human Splicing Finder, MaxEntScan, MutationTaster, NetGene2, NNSplice, SpliceSiteFinder-like) predict that the intronic variant reduces the efficiency of the canonical splice donor, consistent with the observed effect on splicing. Based on the above information, the variant is classified as pathogenic. REFERENCES Link to HbVar database for IVS-I-6 (T->C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=826 Breveglieri G et al. Generation and Characterization of a Transgenic Mouse Carrying a Functional Human beta -Globin Gene with the IVSI-6 Thalassemia Mutation. Biomed Res Int. 2015:687635. Efremov D et al. Possible factors influencing the haemoglobin and fetal haemoglobin levels in patients with beta-thalassaemia due to a homozygosity for the IVS-I-6 (T-->C) mutation. Br J Haematol. 1994; 86(4):824-30. Orkin S et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982; 296(5858):627-31.
Counsyl RCV000415353 SCV000677946 pathogenic beta Thalassemia 2015-07-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763252 SCV000893889 pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000415353 SCV000914518 pathogenic beta Thalassemia 2018-08-14 criteria provided, single submitter clinical testing The HBB c.92+6T>C variant, widely known as IVS-I-6, is a well-described and common cause of beta thalassemia, with the greatest frequency among Mediterranean and Middle-Eastern populations, accounting for up to 48.5 percent of disease alleles in some populations (El-Latif et al. 2002; Origa et al. 2015). Individuals who are homozygous or compound heterozygous for the c.92+6T>C variant display a range of disease phenotypes from beta thalassemia intermedia to beta thalassemia major (El-Latif et al. 2002; Origa et al. 2015). Across a selection of available literature, the c.92+6T>C variant has been identified in a homozygous state in at least 42 patients and in a compound heterozygous state with a second pathogenic variant in at least 21 individuals, with symptoms ranging from non-transfusion dependent beta thalassemia to transfusion dependent beta thalassemia major (El-Latif et al. 2002; Kakavas et al. 2006; El-Gawhary et al. 2007; Bell et al. 2011). Control data are unavailable for the c.92+6T>C variant, which is reported at a frequency of 0.00046 in the Other population of the Genome Aggregation Database. RT-PCR experiments demonstrated that the c.92+6T>C variant produces aberrantly spliced mRNA transcripts in samples derived from homozygous patients or a transgenic mouse line (TG-β-IVSI-6) (Breveglieri et al. 2015). Haplotype analysis has also shown the c.92+6T>C variant is linked to two beta-globin cluster haplotypes, Mediterranean VI and VII (El-Latif et al. 2002; Chen et al. 2015). Based on the collective evidence, the c.92+6T>C variant is classified as pathogenic for beta thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000417932 SCV000963545 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs35724775, ExAC 0.03%). This variant has been observed to segregate with beta thalassemia in families (PMID: 7668219). It also has been observed in several homozygous and compound heterozygous individuals affected with beta thalassemia (PMID: 2200760, 21797703, 25856402, 28366028, 28670940, 28391758, 6280057). This variant is also known as IVS-1 çƒ, IVS-I-6 T>C, and IVSI-6 in the literature. ClinVar contains an entry for this variant (Variation ID: 15450). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this sequence change disrupts normal mRNA splicing (PMID: 6188062, 26097845). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004347 SCV001163282 pathogenic Hb SS disease criteria provided, single submitter clinical testing
OMIM RCV000016708 SCV000036978 pathogenic Beta-plus-thalassemia 1982-04-15 no assertion criteria provided literature only
GeneReviews RCV000415353 SCV000040718 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Baylor Genetics RCV000415353 SCV000328763 pathogenic beta Thalassemia 2015-07-01 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.92+6T>C) and TJP2 (NM_004817.3, c.1243delT homozygous) in one individual with reported features that include prematurity, cholestasis of the liver, mild pulmonic stenosis, chronic anemia of thalassemia, and obstructive sleep apnea. The HBB variant has been previously reported as disease-causing (PMID 20395516, 21797703, 21228398).

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