Submissions for variant NM_000518.5(HBB):c.230del (p.Ala77fs)

dbSNP: rs281864901

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169256	SCV000220545	likely pathogenic	beta Thalassemia	2014-07-23	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508493	SCV000601260	pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169256	SCV000697099	pathogenic	beta Thalassemia	2016-08-16	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.230delC (p.Ala77Valfs) 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. The variant of interest was found in controls at an allele frequency of 1/121392, which does not exceed the estimated maximal expected allele frequency for a pathogenic HBB variant of 1/89 (0.0111803). The variant of interest has been reported in multiple affected individuals via publications, along with reputable databases/clinical laboratories citing the variant as "pathogenic/likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000508493	SCV001592413	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala77Valfs*13) 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 (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3408672, 26076395). ClinVar contains an entry for this variant (Variation ID: 15420). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508493	SCV005875966	pathogenic	not provided	2024-09-23	criteria provided, single submitter	clinical testing	The HBB c.230del; p.Ala77ValfsTer13 variant (also known as Codon 76 (-C) or as Ala76fs when numbered from the mature protein, rs281864901, HbVar ID: 874) is a beta(0) allele reported in the heterozygous state in individuals with microcytic anemia and in the homozygous or compound heterozygous state in individuals with beta-thalassemia major (Danjou 2012, Giambona 2011, Harteveld 2013, HbVar databases and references therein). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 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 database: https://globin.bx.psu.edu/hbvar/menu.html Danjou F et al. Genetic modifiers of beta-thalassemia and clinical severity as assessed by age at first transfusion. Haematologica. 2012 Jul;97(7):989-93. PMID: 22271886. Giambona A et al. The genetic heterogeneity of beta-globin gene defects in Sicily reflects the historic population migrations of the island. Blood Cells Mol Dis. 2011 Apr 15;46(4):282-7. PMID: 21353607. Harteveld CL et al. Mosaic segmental uniparental isodisomy and progressive clonal selection: a common mechanism of late onset beta-thalassemia major. Haematologica. 2013 May;98(5):691-5. PMID: 22983591.
OMIM	RCV000016676	SCV000036946	pathogenic	Beta zero thalassemia	1992-02-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000169256	SCV001244483	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000169256	SCV002089211	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing