ClinVar Miner

Submissions for variant NM_000517.6(HBA2):c.69C>T (p.Gly23=)

gnomAD frequency: 0.00004  dbSNP: rs63751457
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759057 SCV000888138 likely pathogenic not provided 2021-01-13 criteria provided, single submitter clinical testing The variant generates abnormal mRNA splicing and leads to premature termination of alpha-2 globin protein synthesis. It is also associated with alpha(+)-thalassemia (PMID: 15481895 (2004), PMID: 23614625 (2013), PMID: 26365411 (2015)).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002048 SCV001159873 likely pathogenic not specified 2018-08-15 criteria provided, single submitter clinical testing The HBA2 c.69C>T; Gly22Gly variant (rs63751457), also known as Codon 22 C>T, is reported in the literature in several individuals affected with alpha thalassemia and has been reported in trans to several pathogenic variants (Deshpande 2015, Harteveld 2004, Nainggolan 2010, Nainggolan 2013, HbVar database). The Gly22Gly variant is reported in ClinVar (Variation ID: 15687) and is found on two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic splice donor site. Splicing at this cryptic donor site is predicted to cause a frameshift and premature stop codon (Harteveld 2004). Based on available information, this variant is considered to be likely pathogenic. References: HbVar database entry: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2514 Deshpande P et al. Characterization of Clinical and Laboratory Profiles of the Deletional a2-Globin Gene Polyadenylation Signal Sequence (AATAAA?>?AATA-?-) in an Indian Population. Hemoglobin. 2015;39(6):415-8. Harteveld CL et al. An alpha-thalassemia phenotype in a Dutch Hindustani, caused by a new point mutation that creates an alternative splice donor site in the first exon of the alpha2-globin gene. Hemoglobin. 2004 Aug;28(3):255-9. Nainggolan IM et al. Hydrops fetalis associated with homozygosity for Hb Adana [alpha59(E8)Gly-->Asp (alpha2)]. Hemoglobin. 2010;34(4):394-401. Nainggolan IM et al. Interaction of Hb adana (HBA2: c.179G>A) with deletional and nondeletional a(+)-thalassemia mutations: diverse hematological and clinical features. Hemoglobin. 2013;37(3):297-305.
OMIM RCV000016977 SCV000037249 pathogenic Alpha-thalassemia, Dutch type 2004-08-01 no assertion criteria provided literature only
Natera, Inc. RCV001275678 SCV001461036 likely pathogenic alpha Thalassemia 2020-09-16 no assertion criteria provided clinical testing

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