Submissions for variant NM_000518.5(HBB):c.75T>A (p.Gly25=)

gnomAD frequency: 0.00006  dbSNP: rs33951465

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030002	SCV000052657	pathogenic	beta Thalassemia	2025-03-04	criteria provided, single submitter	clinical testing	Variant summary: HBB c.75T>A results in a synonymous change. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 4e-06 in 251294 control chromosomes. c.75T>A has been reported in the literature in multiple individuals affected with Beta Thalassemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing the variant to cause activation of a cryptic donor splice site that leads to 75% decrease in the accumulation of normally processed Beta globin mRNA (Goldsmith_1983). ClinVar contains an entry for this variant (Variation ID: 15459). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508672	SCV000603908	pathogenic	not provided	2024-10-10	criteria provided, single submitter	clinical testing	The HBB c.75T>A; p.Gly25Gly variant (also known as Gly24Gly when numbered from the mature protein or as codon 24 (T>A), rs33951465, HbVar ID: 805) has been reported in individuals with beta thalassemia who were homozygous for the variant or compound heterozygous with another pathogenic variant (see HbVar and ClinVar links, Gonzalez-Redondo 1988, Hattori 1989). This synonymous variant introduces a cryptic acceptor splice site and has been shown to alter splicing by reducing normal beta globin transcripts by about 75 percent (Goldsmith 1983). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Goldsmith ME et al. "Silent" nucleotide substitution in a beta+-thalassemia globin gene activates splice site in coding sequence RNA. Proc Natl Acad Sci U S A. 1983; 80(8):2318-22. PMID: 6572978 Gonzalez-Redondo JM et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. PMID: 2458145 Hattori Y et al. Characterization of beta-thalassemia mutations among the Japanese. Hemoglobin. 1989; 13(7-8):657-70. PMID: 2634667
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508672	SCV000605847	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	The HBB c.75T>A (p.Gly25=) synonymous variant has been reported in the published literature in several individuals affected with beta(+) thalassemia (PMIDs: 2458145 (1988), 2634667 (1989), 20737602 (2010), 23590658 (2013), 28366028 (2017), 29669226 (2018), 31788855 (2020), 36106931 (2022)). This variant is reported to activate a cryptic splice donor site and significantly reduce the amount of normal HBB mRNA produced (PMID: 6572978 (1983)). The frequency of this variant in the general population, 0.0002 (5/24970 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000508672	SCV000940351	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	This sequence change affects codon 25 of the HBB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs33951465, gnomAD 0.02%). This variant has been observed in individual(s) with beta thalassaemia (PMID: 2458145, 2634667, 28366028). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 15459). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004354	SCV001163290	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000030002	SCV001193989	likely pathogenic	beta Thalassemia	2019-12-20	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.75T>A(aka G25=) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2458145, 6572978, 6583702 and 23590658. Classification of NM_000518.4(HBB):c.75T>A(aka G25=) 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.
GeneDx	RCV000508672	SCV002546736	pathogenic	not provided	2024-11-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate abnormal splicing and a decrease of normally processed beta-globin mRNA (PMID: 6572978); In silico analysis supports a deleterious effect on splicing; Also known as Gly24Gly; This variant is associated with the following publications: (PMID: 25087612, 22975760, 29669226, 26044735, 2458145, 2634667, 23590658, 28366028, 6572978)
Fulgent Genetics, Fulgent Genetics	RCV002496383	SCV002813160	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2021-09-16	criteria provided, single submitter	clinical testing
OMIM	RCV000016717	SCV000036987	pathogenic	Beta-plus-thalassemia	1983-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000030002	SCV000040715	not provided	beta Thalassemia		no assertion provided	literature only