ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.287dupA (p.Leu97Alafs) (rs34937014)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029975 SCV000052630 pathogenic beta Thalassemia 2018-08-14 criteria provided, single submitter clinical testing Variant summary: HBB c.287dupA (p.Leu97AlafsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.323dupG/p.Asn109fsX32). The variant was absent in 277156 control chromosomes (gnomAD). c.287dupA has been reported in the literature in multiple individuals affected with Beta Thalassemia Major (Winichagoon_1992, Cai_1996, Doro_2017). 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. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507093 SCV000601267 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002177 SCV001160040 pathogenic not specified 2018-10-12 criteria provided, single submitter clinical testing The Codon 95 (+A) (HBB: c.287dupA; Leu96fs) variant (rs34937014) has been described in the compound heterozygous state in individuals affected with beta thalassemia (see link to HbVar and references therein, Svasti 2002). It is reported as pathogenic in ClinVar (Variation ID: 36309) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Link to HbVar: Svasti S et al. Molecular analysis of beta-thalassemia in South Vietnam. Am J Hematol. 2002 Oct;71(2):85-8.
Invitae RCV000507093 SCV001415981 pathogenic not provided 2019-10-22 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HBB gene (p.Leu97Alafs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acids of the HBB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with beta thalassemia in a family (PMID: 8889595). ClinVar contains an entry for this variant (Variation ID: 36309). This variant disrupts the C-terminus of the HBB protein. Other variant(s) that disrupt this region (p.Asn109Glnfs*32) have been determined to be pathogenic (PMID: 1728311, 1897518, 3683554, 9401495). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029975 SCV001244628 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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