ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.220G>A (p.Asp74Asn) (rs33945705)

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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 RCV000855647 SCV000603915 likely benign not specified 2018-08-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855647 SCV000697095 likely benign not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: HBB c.220G>A (p.Asp74Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 143240 control chromosomes, predominantly at a frequency of 0.00017 within the African or African-American subpopulation in the gnomAD database (v3 genome dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.220G>A is also known as Hb G-Accra or Hb Korle-Bu when found in isolation, and as Hb C-Harlem or Hb C-Georgetown when found in cis with the Hb S mutation. When present in homozygosity, this variant reportedly does not cause hemoglobinopathy, and is considered an unusual hemoglobin rather than an abnormal/harmful hemoglobin (Boi-Doku_1964, Konotey_1968). In compound heterozygosity with HbS, HbC or beta-thal mutations, the variant of interest reportedly causes no apparent sickness and leads to a sickle-cell trait (when in compound heterozygosity with HbS) rather than sickle-cell disease, HbC disease or beta thalassemia, and does not seem to aggravate the mild status of beta thalassemia heterozygosity (Akl_2009, Chico_2004, Huisman_1997, Konotey_1968, van der Padt_2005). Three publications reported experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect (Bookchin_1967, Nagel_1993, Ivanova_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587238 SCV001134215 likely benign not provided 2019-01-18 criteria provided, single submitter clinical testing
OMIM RCV000016449 SCV000036717 other HEMOGLOBIN KORLE-BU 2017-12-12 no assertion criteria provided literature only

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