ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.50G>A (p.Gly17Asp) (rs33962676)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282304 SCV000603935 benign none provided 2020-07-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755547 SCV000889373 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508165 SCV000917499 uncertain significance not specified 2020-11-06 criteria provided, single submitter clinical testing Variant summary: HBB c.50G>A (p.Gly17Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.50G>A, has been reported in the literature in multiple compound heterozygotes carrying the variant of interest and HbS (e.g. Weatherall_1964, Baglioni_1963, Huisman_1978), and at least 3 of these individuals has been stated to have no symptoms suggestive of anemia or sickle-cell crisis during several years of follow up (Weatherall_1964). A functional study, which measured the rate of change of blood viscosity during deoxygenation demonstrated that blood from a compound heterozygote, behaved similarly to that of sickle-cell carriers, i.e. the variant didn't contribute to sickling (Weatherall_1964, Charache_1964). The variant also has been reported in at least 3 compound heterozygotes who carried a beta-thalassemia allele (Musumeci_1979, Arribalzaga_1996), these individuals had hematological parameters largely similar to individuals with beta-thalassemia trait. Functional studies performed on samples from two of these individuals, indicated normal oxyhemoglobin dissociation curves and P50 values, similar to thalassemia carriers (Arribalzaga_1996). Other functional studies noted no Heinz-body formation, or instability, in addition, oxygen affinity, Bohr-effect, and cooperativity, were all noted to be similar to normal (e.g. Musumeci_1979, Arribalzaga_1996). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these laboratories classified the variant as benign, while the other laboratory called the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
OMIM RCV000016400 SCV000036668 other HEMOGLOBIN J (BALTIMORE) 2017-12-12 no assertion criteria provided literature only

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