ClinVar Miner

Submissions for variant NM_000517.4(HBA2):c.142G>C (p.Asp48His)

gnomAD frequency: 0.00003  dbSNP: rs281864834
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001544589 SCV000885546 likely pathogenic not provided 2022-10-24 criteria provided, single submitter clinical testing The Hb Hasharon variant (HBA2 c.142G>C; p.Asp48His variant, also known as Asp47His when numbered from the mature protein, HbVarID: 65, rs281864834), also known as Hb Sealy and Hb L-Ferrara, is reported in the literature in multiple families of Jewish, Italian and Middle Eastern descent (Charache 1969, Gilad 2017, Kimura 2015, Nagel 1969, Pich 1978, Schneider 1968). Individuals heterozygous for this variant have lower levels of the Hb Hasharon alpha chain than expected (Schneider 1968, Charache 1969), and some have been reported to have microcytosis and hypochromia (Kimura 2015). Functional characterization of Hb Hasharon indicates that the variant alpha chain has reduced stability in vitro (Charache 1969) and in vivo (Molchanova 1994). This variant is found in the general population with an overall allele frequency of 0.009% (12/126964 alleles) in the Genome Aggregation Database. The aspartate at codon 48 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL:0.789). Based on available information, the variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Charache S et al. Hemoglobin Hasharon (alpha-2-47 his(CD5)beta-2): a hemoglobin found in low concentration. J Clin Invest. 1969; 48(5):834-47. PMID: 5780195. Gilad O et al. Molecular diagnosis of alpha-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562. PMID: 28160324. Kimura E et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015; 37(2):103-8. PMID: 25818820. Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994; 88(2):300-6. PMID: 7803274. Nagel R et al. Hemoglobin L Ferrara in a Jewish family associated with a hemolytic state in the propositus. Blood. 1969; 34(2):157-65. PMID: 5794113. Pich P et al. Interaction between Hb Hasharon and alpha-thalassemia: an approach to the problem of the number of human alpha loci. Blood. 1978; 51(2):339-46. PMID: 620088. Schneider R et al. Hemoglobin sealy (alpha 2-47His-beta 2): a new variant in a Jewish family. Am J Hum Genet. 1968; 20(2):151-6. PMID: 5643179.
GeneDx RCV001544589 SCV001763748 pathogenic not provided 2021-01-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect; in-vivo studies show percentage of the mutant Hb decreased with time, supporting instability of the mutant Hb in vivo (Charache et al., 1969); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25818820, 620088, 5643179, 5794113, 5780195, 2752146, 5587575, 28160324, 7803274, 31553106)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001544589 SCV002047307 uncertain significance not provided 2022-12-15 criteria provided, single submitter clinical testing The c.142G>C (p.Asp48His) variant has been reported to be mildly unstable (PMID: 5780195 (1969), 7803274 (1994)). Individuals who are heterozygous for this variant have normal clinical presentations. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001275680 SCV005204955 pathogenic alpha Thalassemia 2024-06-10 criteria provided, single submitter clinical testing Variant summary: HBA2 c.142G>C (p.Asp48His), also reported as "hemoglobin Hasharon", "a2 47 his" and "Hasharon [47(CE5)Asp>His]", results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 126964 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HBA2 causing Alpha Thalassemia (9.5e-05 vs 0.0056). c.142G>C has been reported in the literature in multiple bi-allelic or heterozygous individuals affected with Alpha Thalassemia, microcytosis and hypochromia (examples: Gilad_ 2017, Kimura_ 2015, Silva_ 2013). The following publications have been ascertained in the context of this evaluation (PMID: 5780195, 28160324, 25818820, 7803274, 23741188, 20309827). ClinVar contains an entry for this variant (Variation ID: 15636). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000016910 SCV000037181 other HEMOGLOBIN L (FERRARA) 2018-05-21 no assertion criteria provided literature only
OMIM RCV000016911 SCV000037182 other HEMOGLOBIN HASHARON 2018-05-21 no assertion criteria provided literature only
OMIM RCV000016912 SCV000037183 other HEMOGLOBIN SINAI 2018-05-21 no assertion criteria provided literature only
OMIM RCV000016913 SCV000037184 other HEMOGLOBIN SEALY 2018-05-21 no assertion criteria provided literature only
Natera, Inc. RCV001275680 SCV001461038 likely pathogenic alpha Thalassemia 2020-09-16 no assertion criteria provided clinical testing

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