ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.223G>A (p.Gly75Ser)

gnomAD frequency: 0.00002  dbSNP: rs33916541
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589565 SCV000697096 uncertain significance not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: HBB c.223G>A (p.Gly75Ser) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.223G>A has been reported in the literature in individuals predicted to be carriers for beta-thalassemia (Giambona_2008,2011, Mosca_2008), however, to our knowledge, the variant has not been reported in individuals affected by the disease. These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001283986 SCV001469519 uncertain significance not provided 2024-09-28 criteria provided, single submitter clinical testing The HBB c.223G>A (p.Gly75Ser) variant has been reported in the published literature in individuals with normal hematological indices (PMID: 18603555 (2008)), as well as in individuals predicted to be carriers of beta-thalassemia (PMIDs: 21353607 (2011) and 18486569 (2008)). While the variant is described as having normal stability, heterozygosity for this variant is associated with mild hemolytic anemia and reticulocytosis (HbVar (http://globin.bx.psu.edu/)). The frequency of this variant in the general population, 0.000031 (4/129152 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc. RCV001272125 SCV001453778 uncertain significance beta Thalassemia 2020-09-16 no assertion criteria provided clinical testing

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