ClinVar Miner

Submissions for variant NM_000517.6(HBA2):c.*92A>G

gnomAD frequency: 0.00002  dbSNP: rs63750067
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507591 SCV000601205 pathogenic not provided 2023-08-10 criteria provided, single submitter clinical testing This pathogenic variant changes the polyadenylation signal of the alpha2-globin gene from AATAAA to AATGAA and is associated with alpha-thalassemia. In the published literature, this variant has been reported in individuals with alpha thalassemia (PMID: 29627922 (2018)) and Hb H disease as homozygous and compound heterozygous with other pathogenic alpha-globin variants (PMIDs: 11410420 (2001), 7734346 (1995), 7701914 (1994), 1581238 (1992), 1281602 (1992)). Functional studies report this variant results nonfunctional and unstable mRNA (PMIDs: 1581238 (1992), 1281602 (1992)). Based on the available information, the variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507591 SCV000603882 pathogenic not provided 2023-06-30 criteria provided, single submitter clinical testing The PolyA (A->G) variant (HBA2: c.*92A>G, rs63750067), has been reported in multiple families with Hb H disease when homozygous or in-trans with a double gene deletion (Ma 2001, Thein 1988, Yuregir 1992, HbVar database and references therein). This variant is also reported in ClinVar (Variation ID: 15647). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant is located in the polyadenylation signal of HBA2, and is predicted to reduce the efficiency of polyadenylation of the globin transcript. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database for PolyA (A->G): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1071 Ma ES et al. Interaction between (--SEA) alpha-thalassemia deletion and uncommon non-deletional alpha-globin gene mutations in Chinese patients. Haematologica. 2001 May;86(5):539-40. PMID: 11410420. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. PMID: 3337900. Yuregir G et al. Hb H disease in a Turkish family resulting from the interaction of a deletional alpha-thalassaemia-1 and a newly discovered poly A mutation. Br J Haematol. 1992; 80(4):527-32. PMID: 1581238.
GeneDx RCV000507591 SCV002575801 pathogenic not provided 2024-12-24 criteria provided, single submitter clinical testing Also known as Poly A2, poly(A), and poly A signal variant; Located in a regulatory region; in the absence of functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 37644014, 34272389, 1581238, 34426522, 3337900, 29627922, 27199182, 11410420, 7734346, 31286593, 7701914, 1281602, 37745687)
Fulgent Genetics, Fulgent Genetics RCV002476983 SCV002792390 pathogenic Heinz body anemia; alpha Thalassemia; Hemoglobin H disease; Erythrocytosis, familial, 7 2024-04-24 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV003989291 SCV004806179 likely pathogenic Hemoglobin H disease 2024-03-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017256 SCV004848831 pathogenic beta Thalassemia 2022-11-03 criteria provided, single submitter clinical testing The c.*92A>G variant in HBA2, has been reported in multiple families with Hb H disease (both in the homozygous and in the compound heterozygous state (in trans with a double gene deletion) (selected references: Ma 2001 PMID: 11410420, Thein 1988 PMID: 3337900, Yuregir 1992 PMID: 1581238, HbVar database http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1071). This variant has also been reported in ClinVar (Variation ID: 15647). This variant has been identified in 2/68002 European and in 2/4630 South Asian chromosomes by gnomAD. The variant is located in the polyadenylation signal of HBA2, and is predicted to reduce the efficiency of polyadenylation of the globin transcript. Other variants (e.g., c*94A>G) affecting the polyadenylation signal of HBA2 have been reported in individuals with Hb H disease and have been classified as Pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hb H disease. ACMG/AMP Criteria applied: PM3 Very strong, PM2_supporting, PP3).
OMIM RCV000016933 SCV000037204 pathogenic Alpha-thalassemia-2, nondeletional 1992-04-01 no assertion criteria provided literature only
OMIM RCV000022604 SCV000043893 pathogenic Hemoglobin H disease, nondeletional 1992-04-01 no assertion criteria provided literature only
Natera, Inc. RCV001831575 SCV002093854 pathogenic alpha Thalassemia 2021-01-19 no assertion criteria provided clinical testing

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