Submissions for variant NM_000518.5(HBB):c.143dup (p.Asp48fs)

dbSNP: rs35894115

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505977	SCV000601249	pathogenic	not provided	2017-06-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000016744	SCV000697083	pathogenic	beta Thalassemia	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.143dupA (p.Asp48Glufs) 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.143_146dupATCT/p.Thr51fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121384 control chromosomes. However, it has been reported homozygously in multiple affected individuals with BTHAL-MJR. In addition, multiple reputable databases listed this variant as pathogenic. Moreover, variants involving the same and nearby neucleotides have been reported in affected individuals such as variants c.143A>T, c.143_146dupATCT, c.146T>G, and c.146T>C, suggesting the functional importance of this chromosomal region. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505977	SCV002049808	pathogenic	not provided	2021-02-24	criteria provided, single submitter	clinical testing	The Codon 47 (+A) variant (HBB: c.143dupA; p.Asp48GlufsTer6, also known as Asp47fs when numbered from the mature protein, rs35894115) is reported in individuals affected with beta(0) thalassemia (see link to HbVar, Bibi 2006, Boudrahem-Addour 2009, Hussain 2017, Losekoot 1990). This variant is also reported in ClinVar (Variation ID: 15485), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for Codon 47 (+A): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=856 Bibi A et al. Detection of two rare beta-thalassemia alleles found in the Tunisian population: codon 47 (+A) and codons 106/107 (+G). Hemoglobin. 2006;30(4):437-47. Boudrahem-Addour N et al. Molecular heterogeneity of beta-thalassemia in Algeria: how to face up to a major health problem. Hemoglobin. 2009;33(1):24-36. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. Losekoot M et al. A novel frameshift mutation (FSC 47 (+A)) causing beta-thalassemia in a Surinam patient. Hemoglobin. 1990;14(4):467-70.
OMIM	RCV000016744	SCV000037014	pathogenic	beta Thalassemia	1990-01-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000016744	SCV001244615	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000016744	SCV002089220	pathogenic	beta Thalassemia	2017-08-17	no assertion criteria provided	clinical testing