ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.75T>A (p.Gly25=) (rs33951465)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508672 SCV000603908 pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing The HBB c.75T>A; Gly24Gly variant 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 ClinVar database for c.75T>A: Link to HbVar database for c.75T>A: 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. 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. Hattori Y et al. Characterization of beta-thalassemia mutations among the Japanese. Hemoglobin. 1989; 13(7-8):657-70.
Counsyl RCV000030002 SCV000677926 likely pathogenic beta Thalassemia 2015-10-15 criteria provided, single submitter clinical testing
GeneReviews RCV000030002 SCV000040715 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000030002 SCV000052657 pathogenic beta Thalassemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000508672 SCV000940351 likely pathogenic not provided 2018-12-21 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, ExAC 0.01%). This variant has been observed in individuals with beta thalassaemia (PMID: 28366028, 2458145, 2634667). 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 c.72T>A, p.Gly24Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 15459). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 6572978). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000016717 SCV000036987 pathogenic Beta-plus-thalassemia 1983-04-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508672 SCV000605847 pathogenic not provided 2016-11-12 criteria provided, single submitter clinical testing

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