Submissions for variant NM_000518.5(HBB):c.-78A>G

gnomAD frequency: 0.00001  dbSNP: rs33931746

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029960	SCV000052615	pathogenic	beta Thalassemia	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506257	SCV000601318	pathogenic	not provided	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506257	SCV001156561	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	The c.-78A>G variant (also known as -28A>G, rs33931746, HbVar ID: 769) is a common beta+ thalassemia variant found in Asian populations (see HbVar link, Yamsri 2011), and has been reported in an individual with beta thalassemia who was homozygous for the variant (Orkin 1983). In addition, functional characterization of the variant indicates a 3-5 fold reduction of beta globin mRNA (Orkin 1983). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The c.-78A>G variant is located in a conserved region of the beta globin gene promoter and is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Orkin SH et al. ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 1983 Jul 25;11(14):4727-34. PMID: 6308558. Yamsri S et al. Genotype and phenotype characterizations in a large cohort of beta-thalassemia heterozygote with different forms of alpha-thalassemia in northeast Thailand. Blood Cells Mol Dis. 2011 Aug 15;47(2):120-4. PMID: 21664157.
Baylor Genetics	RCV001004362	SCV001163300	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000029960	SCV001193862	likely pathogenic	beta Thalassemia	2019-12-09	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.-78A>G(aka -28A>G) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is a beta-plus variant associated with beta thalessemia. Sources cited for classification include the following: PMID 8435318, 9160698 and 6308558. Classification of NM_000518.4(HBB):c.-78A>G(aka -28A>G) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000506257	SCV001224372	pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs33931746, gnomAD 0.06%). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 2014803, 8435318, 20035706, 28385923). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -28A>G. ClinVar contains an entry for this variant (Variation ID: 15471). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HBB function (PMID: 6308558). For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795422	SCV005416417	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PS3_Moderate+PP4
Fulgent Genetics, Fulgent Genetics	RCV005049374	SCV005684737	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000016729	SCV000036999	pathogenic	Beta-plus-thalassemia	1983-07-25	no assertion criteria provided	literature only
GeneReviews	RCV000029960	SCV000040701	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029960	SCV001244522	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000029960	SCV002091629	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing