ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.85dup (p.Leu29fs) (rs35532010)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169441 SCV000220858 likely pathogenic beta Thalassemia 2014-11-06 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508423 SCV000601323 pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780308 SCV000917475 pathogenic Hemoglobinopathy 2018-04-27 criteria provided, single submitter clinical testing Variant summary: HBB c.85dupC (p.Leu29ProfsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 277176 control chromosomes (gnomAD and publications). The variant, c.85dupC, has been reported in the literature in multiple individuals affected with Beta Thalassemia Major. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000508423 SCV000953848 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu29Profs*16) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with beta thalassaemia (PMID: 1850955, 2014803). This variant is also known as 27-28insC. ClinVar contains an entry for this variant (Variation ID: 15432). Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002231 SCV001160106 pathogenic not specified 2018-11-13 criteria provided, single submitter clinical testing The HBB c.85dupC; Leu28fs variant (rs35532010), also known as Codons 27/28 (+C), is reported in the literature in multiple individuals affected with beta-thalassemia major in the compound heterozygous state with another pathogenic HBB variant (Lin 1991, Liu 2011, HbVar and references therein). The Leu28fs variant has also been described in beta-thalassemia minor patients without additional reported variants (Liu 2011, HbVar and references therein). This variant is reported as pathogenic/likely pathogenic by several laboratories in ClinVar (Variation ID: 15432), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the Leu28fs variant is considered to be pathogenic. References: Link to HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=810 Lin LI et al. The spectrum of beta-thalassemia mutations in Taiwan: identification of a novel frameshift mutation. Am J Hum Genet. 1991 Apr;48(4):809-12. Liu SC et al. Molecular lesion frequency of hemoglobin gene disorders in Taiwan. Hemoglobin. 2011;35(3):228-36.
Baylor Genetics RCV001004352 SCV001163287 pathogenic Hb SS disease criteria provided, single submitter clinical testing
OMIM RCV000016689 SCV000036959 pathogenic beta^0^ Thalassemia 2017-12-12 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000169441 SCV001244427 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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