ClinVar Miner

Submissions for variant NC_000011.10:g.5227142G>A (rs281864518)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985736 SCV001134211 likely pathogenic not provided 2019-03-15 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/280600 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Nucleotide conservation is uninformative.
Integrated Genetics/Laboratory Corporation of America RCV001078347 SCV001426876 pathogenic beta Thalassemia 2020-07-23 criteria provided, single submitter clinical testing Variant summary: HBB c.-121C>T is located in the untranscribed promoter region upstream of the HBB gene. The variant was absent in 31398 control chromosomes. c.-121C>T (also reported as legacy name c.-71C>T) has been reported in the literature in at least one individual affected with Beta Thalassemia Intermedia (e.g. Verma_2007, Akbari_2008) and has also been reported as associated with borderline HbA2 levels in heterozygous carriers (e.g. Al Zadajali_2011, Al Moamen_2013). In addition, there are multiple citations of this variant in trans with the sickle cell allele (HBB: c.20A>T), resulting in almost equal levels of HbA and HbS which is distinct from carriers of either this variant or the sickle cell allele in isolation (e.g. Al Zadajazi_2011, Al Moamen_2013). These data indicate that the variant is likely to be associated with disease. Several publications report in-vitro experimental evidence evaluating an impact on protein function, indicating that promoter activity is reduced in cells with the variant compared to wild-type (e.g. Pirastru_2017, Kirchner_2019). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV001078347 SCV001244535 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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