ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.323dup (p.Asn109fs) (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 2017-06-30 criteria provided, single submitter clinical testing
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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002348 SCV001160252 pathogenic not specified 2019-03-05 criteria provided, single submitter clinical testing The HBB c.323dupG; p.Asn109fs 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): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=945 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.
Invitae RCV000506185 SCV001384504 likely pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HBB gene (p.Asn109Glnfs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acids of the HBB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with thalassemia (PMID: 3683554, 9401495, 1897518, 1728311). This is also known as 106/107(+G) in the literature. 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: 25666204, 24616059, 24245819, 2895770). 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.
OMIM RCV000016668 SCV000036938 pathogenic beta^0^ 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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