ClinVar Miner

Submissions for variant NM_000517.4(HBA2):c.142G>C (p.Asp48His) (rs281864834)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757355 SCV000885546 likely pathogenic none provided 2020-01-16 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, 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). Although it has not been associated with alpha-thalassemia, 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 (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the variant is considered to be likely pathogenic. References: Link to HbVar database for Hb Hasharon: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=65 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. Gilad O et al. Molecular diagnosis of a-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562. 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. 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. 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. 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. 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.
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)
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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