ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.52A>T (p.Lys18Ter) (rs33986703)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507505 SCV000603897 pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing The HBB c.52A>T; Lys17Ter variant, also known as Codon 17 (A>T), has been reported in multiple individuals with beta thalassemia, and is considered a beta(0) thalassemia variant (HbVar database and references therein). It introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the Lys17Ter variant is classified as pathogenic. REFERENCES Link to HbVar for Lys17Ter: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=800
Counsyl RCV000020337 SCV000677996 pathogenic beta Thalassemia 2017-06-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763255 SCV000893892 pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000507505 SCV000890267 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing The K18X variant in the HBB gene has been reported previously in association with beta thalassemia (Panayasai et al., 2015; Wang et al.., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The K18X variant is observed in 11/18852 (0.0583%) alleles from individuals of East Asian background in large population cohorts, with no homozygotes identified (Lek et al., 2016). We interpret K18X as a pathogenic variant.
GeneReviews RCV000020337 SCV000040713 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000020337 SCV000697138 pathogenic beta Thalassemia 2016-07-28 criteria provided, single submitter clinical testing Variant summary: The HBB c.52A>T (p.Lys18X) 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.85dupC/p.Leu29fsX16). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121842 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in many BTHAL patients (mostly East Asian) both homozygously and in compound heterozygosity with other pathogenic variant. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000507505 SCV000945919 pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HBB gene (p.Lys18*). While it is expected to result in an absent or disrupted protein product, an alternate in-frame methionine (p.Met56, also known as p.Met55) downstream of the initiator codon could potentially rescue the translation initiation (PMID: 21389146). This variant is present in population databases (rs33986703, ExAC 0.02%). This variant has been observed in individual affected with beta thalassemia (PMID: 88735, 26029792, 24857915) and is present on more than 10% beta thalassemia chromosomes from the Asian population (PMID: 29695942, 25849334, 25089872, 20412082). This variant is also known as "Codon 17 (A->T)" and "AAG(Lys)->TAG(stop codon) beta0" in the literature. ClinVar contains an entry for this variant (Variation ID: 15401). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016655 SCV000036924 pathogenic beta^0^ Thalassemia 2000-01-01 no assertion criteria provided literature only

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