Submissions for variant NM_000518.5(HBB):c.93-3T>G

dbSNP: rs34527846

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222330	SCV000052666	pathogenic	Beta thalassemia intermedia	2022-03-02	criteria provided, single submitter	clinical testing	Variant summary: HBB c.93-3T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 252420 control chromosomes. c.93-3T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (example, Wong_1989, Chiou_1993, Ho_1998, Sinha_2009, Al-Allawi_2014, Hassan_2015, Hussain_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The The ITHANET community portal has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477023	SCV002774341	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	The variant found in at least one symptomatic individual. The variant is predicted to negatively affect a known splice site. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002477023	SCV004563859	likely pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	The HBB: c.93-3T>G variant (also known as IVS-I-128 (T->G), rs34527846, HbVar ID: 829) is reported in the compound heterozygous state in individuals with beta (+) thalassemia (Chiou 1993, Hussain 2017, Wong 1989, see link to HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 36341), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Chiou SS et al. Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. Br J Haematol. 1993 Jan;83(1):112-7. PMID: 8435318. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Wong C et al. Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914-8. PMID: 2920213.
OMIM	RCV000016710	SCV000036980	pathogenic	Beta-plus-thalassemia	1989-03-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000030011	SCV001244584	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Genetic Laboratory, Salmaniya Medical Complex	RCV000030011	SCV002073353	pathogenic	beta Thalassemia		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000030011	SCV002089235	pathogenic	beta Thalassemia	2021-03-25	no assertion criteria provided	clinical testing