Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PM2_SupportingPP5_Very_Strong
The NM_000518(HBB):c.79G>T(p.Glu27Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Verdict is Pathogenic. Variant got 17 ACMG points.
GnomAD3 genomesCov.: 32
Submissions by phenotype
|Pathogenic, criteria provided, single submitter||clinical testing||ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories||Mar 17, 2021||The Codon 26 (G>T) variant (HBB: c.79G>T; p.Glu27Ter, also known as Glu26Ter when numbered from the mature protein, rs33950507) 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 general population databases (Exome Variant Server, 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 link to Codon 26 (G>T): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=808 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. -|
|Pathogenic, criteria provided, single submitter||clinical testing||Invitae||Aug 12, 2021||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). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 1974422). This variant is also known as codon 26 GAG>TAG. ClinVar contains an entry for this variant (Variation ID: 38650). For these reasons, this variant has been classified as Pathogenic. -|
|Pathogenic, criteria provided, single submitter||clinical testing||Quest Diagnostics Nichols Institute San Juan Capistrano||Jun 30, 2017||- -|
|Pathogenic, no assertion criteria provided||clinical testing||Natera, Inc.||Aug 17, 2017||- -|
|Pathogenic, no assertion criteria provided||curation||The ITHANET community portal, The Cyprus Institute of Neurology and Genetics||Nov 25, 2019||- -|
|Pathogenic, criteria provided, single submitter||clinical testing||Counsyl||Jun 04, 2018||- -|
|Pathogenic, criteria provided, single submitter||clinical testing||Women's Health and Genetics/Laboratory Corporation of America, LabCorp||Dec 14, 2017||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. -|
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