ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.118C>T (p.Gln40Ter) (rs11549407)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508060 SCV000603892 pathogenic not specified 2017-06-21 criteria provided, single submitter clinical testing
Baylor Miraca Genetics Laboratories, RCV000379715 SCV000328728 pathogenic beta Thalassemia 2016-02-10 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.118C>T) and KANSL1 (NM_001193466.1, c.985_995del) in one individual with reported features of delayed motor milestones, delayed speech, intellectual disability, dysmorphic features, familial short stature, minor beta-thalassemia, eye anomalies (strabismus, nearsighted) and cafe au lait spot on right upper chest. Brain MRI showed asymmetric prominent ventricles, possible undermyelination and amygdalo/hippocampal dysgenesis. The same variant has been found in 4 additional individuals with beta thalassemia trait.
Counsyl RCV000379715 SCV000678168 pathogenic beta Thalassemia 2015-11-24 criteria provided, single submitter clinical testing Q40* is classified as a beta-zero mutation.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254827 SCV000331533 pathogenic not provided 2016-04-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763250 SCV000893887 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 RCV000254827 SCV000321762 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The Q40X pathogenic variant in the HBB gene has been reported previously using alternate nomenclature (Q39X) in trans with a second HBB variant in several individuals with beta-thalassemia (Ghedira et al., 2011; Herrera et al., 2015). Functional studies demonstrate significantly reduced mRNA expression level in R40X transfected Hela cells with no protein detected, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay (Neu-Yilik et al., 2011). The Q40X variant is observed in 77/126638 (0.06%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). We interpret Q40X as a pathogenic variant.
GeneReviews RCV000379715 SCV000040703 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000379715 SCV000595094 pathogenic beta Thalassemia 2016-03-15 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000379715 SCV000584091 pathogenic beta Thalassemia 2016-02-11 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000379715 SCV000697073 pathogenic beta Thalassemia 2016-04-08 criteria provided, single submitter clinical testing Variant summary: The c.118C>T variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein, which is a commonly known diease mechanism in hemoglobinopathy. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.217dupA, c.230delC, c.251delG, etc. ). This variant is found in 51/121354 control chromosomes at a frequency of 0.0004203, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant is a well-known common pathogenic variant in Sardinian and other populations (Danjou_2012, Sirdah_2013). Multiple reputable databases classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.
Invitae RCV000254827 SCV000950883 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln40*) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs11549407, ExAC 0.07%). This variant has been observed as homozygous or in combination with other HBB variants in individuals affected with beta-thalassemia (PMID: 8095930, 25572186, 28366028, 27427187). This variant is also known as p.Gln39X in the literature. ClinVar contains an entry for this variant (Variation ID: 15402). Experimental studies have shown that this nonsense variant, referred as NS39, is subject to nonsense-mediated decay (NMD), resulting in little or no detectable mRNA and protein expression in vitro (PMID: 21389146). Loss-of-function variants in HBB are known to be pathogenic (PMID: 7510147, 19269866, 23637309). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016656 SCV000036925 pathogenic beta^0^ Thalassemia 1992-02-01 no assertion criteria provided literature only

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