Submissions for variant NM_000518.5(HBB):c.79G>T (p.Glu27Ter)

dbSNP: rs33950507

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507549	SCV000601319	pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000674991	SCV000800412	pathogenic	beta Thalassemia	2018-06-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507549	SCV000885563	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	The Codon 26 (G>T) variant (HBB: c.79G>T; p.Glu27Ter, also known as Glu26Ter when numbered from the mature protein, rs33950507, HbVar ID: 808) is reported in an individual with beta thalassemia that also harbored the HbE variant (HbVar database and references therein). In testing performed at ARUP Laboratories, this variant has also been observed in trans to a frameshift variant in an individual with severe anemia. The p.Glu27Ter variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Consistent with predictions, functional studies demonstrate an absence of beta globin protein and mRNA in cells expressing this variant (Neu-Yilik 2011). Based on available information, this variant is considered to be pathogenic. References: HbVar database link: https://globin.bx.psu.edu/hbvar/menu.html Neu-Yilik G et al. Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA. 2011 May;17(5):843-54. PMID: 21389146.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781460	SCV000919497	pathogenic	Hemoglobinopathy	2017-12-14	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.79G>T (p.Glu27X, also known as CD26 G>T) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.85dupC/p.Leu29fsX16, c.110delC/p.Pro37fsX25, etc.). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 277088 control chromosomes. It has been reported in multiple affected individuals. Variant involving the same neucleotide c.79G>A/p.Glu27Lys is a common HbE variant and the region around codon 26 has been suggested as mutation hotspot(Fucharoen_1990). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000507549	SCV001582051	pathogenic	not provided	2021-04-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with beta thalassemia (PMID: 1974422). It is known as codon 26 GAG>TAG. ClinVar contains an entry for this variant (Variation ID: 38650). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu27*) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309).
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000674991	SCV001244658	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000674991	SCV002091594	pathogenic	beta Thalassemia	2017-08-17	no assertion criteria provided	clinical testing