Submissions for variant NM_000518.5(HBB):c.287dup (p.Leu97fs)

dbSNP: rs34937014

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	RCV000029975	SCV000052630	pathogenic	beta Thalassemia	2018-08-14	criteria provided, single submitter	clinical testing	Variant summary: HBB c.287dupA (p.Leu97AlafsX6) 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 (eg. c.323dupG/p.Asn109fsX32). The variant was absent in 277156 control chromosomes (gnomAD). c.287dupA has been reported in the literature in multiple individuals affected with Beta Thalassemia Major (Winichagoon_1992, Cai_1996, Doro_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507093	SCV000601267	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	The HBB c.287dup (p.Leu97Alafs*6) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia, and is commonly found in individuals with beta-thalassemia in Southeast Asia (PMIDs: 12353305 (2002), 8889595 (1996), 1515453 (1992)). Previous names for this pathogenic variant include Codon 95 (+A), c.287_288insA and c.287dupA.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000507093	SCV001415981	pathogenic	not provided	2021-03-10	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the HBB gene (p.Leu97Alafs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acids of the HBB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with beta thalassemia in a family (PMID: 8889595). ClinVar contains an entry for this variant (Variation ID: 36309). This variant disrupts the C-terminus of the HBB protein. Other variant(s) that disrupt this region (p.Asn109Glnfs*32) have been determined to be pathogenic (PMID: 1728311, 1897518, 3683554, 9401495). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029975	SCV001244628	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000029975	SCV002089200	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing