Submissions for variant NM_000518.5(HBB):c.-78A>G (rs33931746)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	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	RCV001000122	SCV001156561	pathogenic	not specified	2018-08-24	criteria provided, single submitter	clinical testing	The HBB c.-78A>G variant (commonly known as -28 (A->G)) 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 listed in the dbSNP database (rs33931746), and is not observed in the general population (1000 Genomes Project). 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 for -28 (A->G): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=769 Orkin SH et al. ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 1983 Jul 25;11(14):4727-34. 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.
Baylor Genetics	RCV001004362	SCV001163300	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Women's Health, 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.
Invitae	RCV000506257	SCV001224372	pathogenic	not provided	2019-12-27	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 not present in population databases (ExAC no frequency). This variant has been observed in individuals with beta thalassemia (PMID: 2014803, 28385923, 8435318, 20035706). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -28A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 15471). This variant has been reported to affect HBB expression (PMID: 6308558). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000016729	SCV000036999	pathogenic	Beta-plus-thalassemia	1983-07-25	no assertion criteria provided	literature only
GeneReviews	RCV000029960	SCV000040701	pathogenic	beta Thalassemia	2015-05-14	no assertion criteria 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