ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.59A>G (p.Asn20Ser) (rs33972047)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508637 SCV000605846 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020338 SCV000697141 pathogenic beta Thalassemia 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The HBB c.59A>G (p.Asn20Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict that this variant strengthens a cryptic 5' splicing donor site and affects normal splicing. This prediction has been confirmed by at least one functional study (Gonzalez-Redondo_1989). This variant has been found in multiple patients with beta thalassemia (Yang_1989 and Rujito_2015) and is absent in 121362 control chromosomes. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000121 SCV001156560 pathogenic not specified 2019-05-02 criteria provided, single submitter clinical testing The Hb Malay variant (HBB: c.59A>G; p.Asn20Ser, also known as Asn19Ser when numbered from the mature protein; rs33972047) is reported in the literature in numerous individuals affected with beta-thalassemia intermedia, either in the homozygous state or in trans to another pathogenic variant (Amran 2017, Ma 2000, Yang 1989, HbVar and references therein). This variant has been reported to segregate with disease in a family and has also been reported in heterozygous individuals with microcytosis and hypochromia (Amran 2017, Yan 1989). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 20 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic donor splice site. Based on available information, the Hb Malay variant is considered to be pathogenic. References: HbVar link to Hb Malay: Amran HS et al. Case Series of Homozygous and Compound Heterozygosity of Hb Malay, the Diagnostic Features and Transfusion Requirements. J Biomed Clin Sci. 2017 Dec;2(2)23-25. Ma SK et al. Beta-thalassemia intermedia caused by compound heterozygosity for Hb Malay (beta codon 19 AAC-->AGC; asn-->Ser) and codons 41/42 (-CTTT) beta(0)-thalassemia mutation. Am J Hematol. 2000 Jul;64(3):206-9. Yang KG et al. Molecular characterization of beta-globin gene mutations in Malay patients with Hb E-beta-thalassaemia and thalassaemia major. Br J Haematol. 1989 May;72(1):73-80.
OMIM RCV000016479 SCV000036747 other HEMOGLOBIN MALAY 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016480 SCV000036748 pathogenic Beta-plus-thalassemia 1989-05-01 no assertion criteria provided literature only
OMIM RCV000016481 SCV000036749 pathogenic Beta-malay-thalassemia 1989-05-01 no assertion criteria provided literature only
GeneReviews RCV000020338 SCV000040714 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only

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