ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.25_26del (p.Lys9fs) (rs35497102)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029972 SCV000052627 pathogenic beta Thalassemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506563 SCV000601261 pathogenic not provided 2016-11-12 criteria provided, single submitter clinical testing
Invitae RCV000506563 SCV000953169 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys9Valfs*14) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs35497102, ExAC 0.01%). This variant has been observed in several individuals with HBB-related conditions (PMID: 3828533, 25405919, 28391758, 26771086). ClinVar contains an entry for this variant (Variation ID: 15413). Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002297 SCV001160183 pathogenic not specified 2018-12-26 criteria provided, single submitter clinical testing The HBB c.25_26delAA; p.Lys9fs variant (also known as Lys8fs when numbered from the mature protein or as codon 8 (-AA)) has been reported in multiple patients with beta-0 thalassemia, both in the homozygous state and in trans to another pathogenic variant (Jalilian 2017, Orkin 1981, HbVar database and references therein). This variant is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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 8 (-AA): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=785 Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. Orkin S et al. Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes. J Biol Chem. 1981; 256(19):9782-4.
Baylor Genetics RCV001004358 SCV001163294 pathogenic Hb SS disease criteria provided, single submitter clinical testing
OMIM RCV000016669 SCV000036939 pathogenic beta^0^ Thalassemia 1995-04-01 no assertion criteria provided literature only
GeneReviews RCV000029972 SCV000040706 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Counsyl RCV000029972 SCV000678156 pathogenic beta Thalassemia 2015-09-03 no assertion criteria provided clinical testing

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