ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-1G>A (rs33952266)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668023 SCV000792565 pathogenic beta Thalassemia 2017-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001199849 SCV001370574 likely pathogenic Hemoglobinopathy 2020-05-14 criteria provided, single submitter clinical testing Variant summary: HBB c.316-1G>A (also described in the literature as IVS-II-850G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251150 control chromosomes (gnomAD). c.316-1G>A has been reported in the literature in homozygous and heterozygous individuals affected with beta-thalassemia (e.g. Al Mosawi_2020). Furthermore, beta-thal trait individuals heterozygous for the variant, were reported with a history of mild anemia and microcytosis (e.g. Curuk_1995, Knott_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the same splice-site nucleotide (c.316-1G>C, c.316-1G>T) have been reported internally and also, in ClinVar and HGMD as pathogenic/likely pathogenic and disease-associated. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
College of Science, Al Muthanna University,Al Muthanna University RCV000668023 SCV000804462 pathogenic beta Thalassemia 2018-07-01 no assertion criteria provided research
College of Science, Al Muthanna University,Al Muthanna University RCV000736022 SCV000864065 pathogenic beta^0^ Thalassemia 2018-01-01 no assertion criteria provided research
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000668023 SCV001244415 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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