ClinVar Miner

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

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254827 SCV000331533 pathogenic not provided 2016-04-21 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
Genetic Services Laboratory,University of Chicago RCV000379715 SCV000595094 pathogenic beta Thalassemia 2016-03-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508060 SCV000603892 pathogenic not specified 2018-07-02 criteria provided, single submitter clinical testing The HBB c.118C>T; p.Gln40Ter variant (also known as Gln39Ter when numbered from the mature protein or as codon 39 C>T) induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This variant is one of the most common Mediterranean beta-0 thalassemia variants (see HbVar link and references therein). REFERENCES Link to HbVar database for Gln39Ter:
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.
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-globin type; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000254827 SCV000950883 pathogenic not provided 2019-12-24 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.
Baylor Genetics RCV001004570 SCV001163654 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000379715 SCV001194055 pathogenic beta Thalassemia 2019-12-10 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.118C>T(Q40*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that Q40* is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 1734721 and 21417574. Classification of NM_000518.4(HBB):c.118C>T(Q40*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000379715 SCV001365782 pathogenic beta Thalassemia 2019-12-04 criteria provided, single submitter clinical testing The p.Gln40X variant, also reported as p.Gln39X, in HBB is a well-known pathogenic variant that has been identified in the homozygous or compound heterozygous state with another pathogenic variant in >300 individuals with beta thalassemia (Rosatelli 1992, Ghedira 2011, Danjou 2012, Sirdah 2013, Herrera 2015, Gallagher 2016, Hussain 2017, Carrocini 2017). It has also been reported by other clinical laboratories in ClinVar (Variation ID 15402). Additionally, it has been identified in 0.062% (80/129120) of European (non-Finnish) chromosomes by gnomAD ( However, this frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 40 and has shown decreased mRNA expression level with no protein detected in p.Arg40X transfected Hela cells, suggesting that the variant undergoes nonsense-mediated mRNA decay (Neu-Yilik et al., 2011). Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197268 SCV001367905 pathogenic Microcytic anemia; Anemia; Abnormality of the hand; Splenomegaly; Thoracic scoliosis; Hypoplasia of the ulna 2019-03-28 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.
OMIM RCV000016656 SCV000036925 pathogenic beta^0^ Thalassemia 1992-02-01 no assertion criteria provided literature only
GeneReviews RCV000379715 SCV000040703 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Baylor Genetics 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.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000379715 SCV001132982 pathogenic beta Thalassemia 2019-08-25 no assertion criteria provided clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000379715 SCV001244540 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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