ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.371_378del (p.Thr124fs)

dbSNP: rs1554917561
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588177 SCV000697127 pathogenic beta Thalassemia 2017-01-05 criteria provided, single submitter clinical testing Variant summary: The HBB c.371_378delCCCCACCA (p.Thr124Serfs) variant results in a premature termination codon. The variant is reported as a dominant BTHAL-causing mutation in literature and in databases (ITHA.net and HbVar). This variant has not been observed in general population. This frame-shift variant was first identified in one Thai B-THAL patient who was negative for other mutations upon screening for gross deletions in alfa gene cluster and all exons and exon-intron boundaries of the beta-globin gene (Fucharoean 1991). No abnormal protein was detected in the patient, suggesting that this beta-globin variant is highly unstable and likely to be degraded soon after translation. The variant was also reported in another patient from the same country who also had dominant beta-thalassemia (Boonyawat 2014).Taken together, the variant is classified to be pathogenic for dominant B-THAL.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002371 SCV001160279 pathogenic not specified 2019-01-30 criteria provided, single submitter clinical testing The HBB: c.371_378delCCCCACCA; p.Thr124fs variant (known as Thr123fs when numbered from the mature protein) (rs1554917561), also known as Codons 123/124/125 (-ACCCCACC), is reported in the literature in several individuals affected with beta-thalassemia (Boonyawat 2014, Fucharoen 1991, HbVar database). Both affected individuals had inclusion bodies observed (Boonyawat 2014, Fucharoen 1991), and one individual with severe disease also carried a mild Hb E variant (Fucharoen 1991). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a frameshift and premature termination codon in the last exon of the HBB gene, which may not lead to nonsense-mediated decay but is expected to create a truncated HBB protein. Hemoglobin analysis of an affected individual with this variant indicated an absence of truncated protein, suggesting this variant is highly unstable (Fucharoen 1991). Based on available information, this variant is considered to be pathogenic. References: HbVar link to Codons 123/124/125: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=953 Boonyawat B et al. Molecular analysis of beta-globin gene mutations among Thai beta-thalassemia children: results from a single center study. Appl Clin Genet. 2014 Dec 10;7:253-8. Fucharoen G et al. Eight-base deletion in exon 3 of the beta-globin gene produced a novel variant (beta khon kaen) with an inclusion body beta-thalassemia trait. Blood. 1991 Jul 15;78(2):537-9.

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