ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000587238 SCV000603915 likely benign not provided 2017-09-06 criteria provided, single submitter clinical testing The Hb G-Accra variant (c.220G>A, Asp73Asn) (rs33945705), also known as Hb Korle Bu, has been reported in two individuals in combination with pathogenic HBB variants (Hb S and Hb C), and in both cases, did not alter the clinical symptoms of the individuals (Konotey-Ahulu 1968, Nagel 1993). An individual homozygous for this variant also experiences no clinical symptoms or defects in red blood cells (Lehmann 1964). The variant is listed in ClinVar (Variation ID: 15244), and observed 5 times in the Genome Aggregation Database general population database (5/277130 alleles). The aspartate at residue 73 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Based on the above information, the Hb G-Accra variant is considered likely benign. References: Link to HbVar database for Hb G-Accra: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=383 Lehmann H et al. Haemoglobin GACCRA. Nature. 1964; 203:363-5. Konotey-Ahulu F et al. Haemoglobin Korle-Bu (beta 73 aspartic acid replaced by asparagine) showing one of the two amino acid substitutions of haemoglobin C Harlem. J Med Genet. 1968; 5(2):107-11. Nagel R et al. Compound heterozygosity for hemoglobin C and Korle-Bu: moderate microcytic hemolytic anemia and acceleration of crystal formation Blood. 1993; 82(6):1907-12.
Integrated Genetics/Laboratory Corporation of America RCV000855647 SCV000697095 likely benign not specified 2019-04-22 criteria provided, single submitter clinical testing Variant summary: HBB c.220G>A (p.Asp74Asn) results in a conservative amino acid change located in the Globin (IPR000971) of 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 1.2e-05 in 251420 control chromosomes (gnomAD). 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 G-Accra or Hb Korle-Bu when found in isolation and as Hb C-Harlem when found in cis with 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 report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Bookchin_1967, Nagel_1993, Ivanova_2001). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000016449 SCV000036717 other HEMOGLOBIN KORLE-BU 2017-12-12 no assertion criteria provided literature only

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