ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.323dup (p.Asn109fs)

dbSNP: rs35225141
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506185 SCV000601289 pathogenic not provided 2021-01-05 criteria provided, single submitter clinical testing The HBB c.323dup (p.Asn109Glnfs*32) pathogenic frameshift variant causes the premature termination of beta globin protein synthesis and is associated with beta-zero-thalassemia (PMID: 23590658 (2013), 21119755 (2009)).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589491 SCV000697119 pathogenic beta Thalassemia 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The c.323dupG (p.Asn109Glnfs) variant in HBB gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC, but is present at a low frequency in gnomAD dataset (0.000007; 2/276928 chrs tested), which does not exceed exceed the estimated maximal expected allele frequency of a pathogenic variant (0.011). The variant has been reported in several affected individuals presented with b-thalassemia major via published reports and is cited by reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic.
Invitae RCV000506185 SCV001384504 likely pathogenic not provided 2021-08-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn109Glnfs*32) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the HBB protein. This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3683554). ClinVar contains an entry for this variant (Variation ID: 439153). This variant disrupts the p.Glu122 amino acid residue in HBB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2895770, 24245819, 24616059, 25666204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506185 SCV002048071 pathogenic not provided 2021-03-24 criteria provided, single submitter clinical testing The HBB c.323dupG; p.Asn109GlnfsTer32 variant (rs35225141), also known as c.321_322insG and Codon 106/107 (+G), has been reported in individuals with beta thalassemia (Hoppe 2013), and found with another pathogenic HBB variant (Wong 1987). This variant is reported as pathogenic in ClinVar (Variation ID: 439153). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating 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 for Codon 106/107 (+G): Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6.
OMIM RCV000016668 SCV000036938 pathogenic Beta zero thalassemia 1987-11-26 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000589491 SCV001244495 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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