ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.130G>T (p.Glu44Ter) (rs33922842)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506797 SCV000601241 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing
Counsyl RCV000665678 SCV000789837 pathogenic beta Thalassemia 2017-02-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506797 SCV000883991 pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing The HBB c.130G>T; Glu43Ter variant (rs33922842), also known as Codon 43 (G>T), is reported in the medical literature in an individual with beta thalassemia who also carried an additional nonsense variant on the opposite chromosome (Atweh 1988, see link to HbVar below). The variant is described as pathogenic in the ClinVar database (Variation ID: 15406). The variant is also listed in the Genome Aggregation Database in 1 out of 246166 alleles. This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In agreement with that prediction, this variant is shown to have reduced mRNA levels when transfected and absent mRNA levels in cells derived from the individual who carried this variant and an additional nonsense variant on the opposite chromosome (Athweh 1988). Considering available information, this variant is classified as pathogenic. References: Link to Glu43Ter in HbVar database: Atweh GF et al. New amber mutation in a beta-thalassemic gene with nonmeasurable levels of mutant messenger RNA in vivo. J Clin Invest. 1988 Aug;82(2):557-61.
Integrated Genetics/Laboratory Corporation of America RCV000780310 SCV000917477 pathogenic Hemoglobinopathy 2017-11-14 criteria provided, single submitter clinical testing Variant summary: The HBB c.130G>T (p.Glu44X) 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.176delC, c.217dupA, c.287dupA, etc.). This variant was found in 1/246166 control chromosomes at a frequency of 0.0000041 (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been found three Chinese BTHAL patients in compound heterozygous state with other pathogenic variants (Atwen_1988, Tan_2006). Two of them were BTHAL major patients who carried this variant in compound heterozygous state with c.127_130delCTTT. In addition, several BTHAL minor individuals who carry this variant in heterozygous state have been reported (Lin_2014, He_2017). The carrier frequency in a large Chinese population was 0.03% (He_2017). A functional analysis showed that the mutant mRNA in vivo must be extremely low (Atwen_1988). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV001004568 SCV001163652 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Invitae RCV000506797 SCV001410344 pathogenic not provided 2019-10-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu44*) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with beta-thalassemia (PMID: 3403716, 25089872). This variant is also known as p.Glu43* in the literature. ClinVar contains an entry for this variant (Variation ID: 15406). This variant has been reported to affect HBB protein function (PMID: 3403716). Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016660 SCV000036929 pathogenic beta^0^ Thalassemia 1988-08-01 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000665678 SCV001244550 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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