Submissions for variant NM_000518.5(HBB):c.271G>T (p.Glu91Ter)

dbSNP: rs33913712

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001078368	SCV001774560	pathogenic	beta Thalassemia	2021-07-23	criteria provided, single submitter	clinical testing	Variant summary: HBB c.271G>T (p.Glu91X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251422 control chromosomes. c.271G>T has been reported in the literature in multiple individuals affected with Beta Thalassemia with features resembling those of beta-thal minor and characteristic hematological findings (example, Fucharoen_1990, Nomura_1990, Hattori_1992). These data indicate that the variant is very likely to be associated with disease. One database (ITHANET) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV003556031	SCV004294099	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu91*) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the HBB protein. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Val127Glufs*8) have been determined to be pathogenic (PMID: 8535446, 31190580). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 15504). This variant is also known as codon 90 (GAG to TAG). This premature translational stop signal has been observed in individual(s) with clinical features of HBB-related conditions (PMID: 1517109, 2214342, 8091935, 31934147).
OMIM	RCV000016766	SCV000037036	pathogenic	Beta zero thalassemia	1992-01-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078368	SCV001244564	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078368	SCV002089202	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing