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

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Total submissions: 10

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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	2024-09-19	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, ClinVar Variation ID 15636), also known as Hb Sealy and Hb L-Ferrara, is reported in the literature in multiple families from differing ethnicities affected with anemia and red blood cell disorder (Charache 1969, de la Fuente-Gonzalo 2019, Gilad 2017, Kimura 2015, Nagel 1969, Pich 1978, Schneider 1968, Warghade 2018). 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 (v2.1.1). 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. de la Fuente-Gonzalo F et al. Characterization of deletional and non-deletional alpha globin variants in a large cohort from Spain between 2009 and 2014. Ann Hematol. 2019 Jul. PMID: 31025160. 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. Warghade S et al. Prevalence of hemoglobin variants and hemoglobinopathies using cation-exchange high-performance liquid chromatography in central reference laboratory of India: A report of 65779 cases. J Lab Physicians. 2018 Jan-Mar. PMID: 29403210.
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	pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	The HBA2 c.142G>C (p.Asp48His) variant (also known as Hb Hasharon) has been reported in the heterozygous state in individuals with normal clinical presentation (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)) or with microcytic anemia (PMID: 5780195 (1969), 31025160 (2019)). Individuals who are homozygous for this variant presented with microcytosis, hypochromia, and polycythemia (PMID: 25818820 (2015)). This variant has been reported to be mildly unstable in experimental studies (PMID: 5780195 (1969), 7803274 (1994)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
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.
Fulgent Genetics, Fulgent Genetics	RCV005016273	SCV005642315	likely pathogenic	Heinz body anemia; alpha Thalassemia; Hemoglobin H disease; Erythrocytosis, familial, 7	2024-04-01	criteria provided, single submitter	clinical testing
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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