ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.20del (p.Glu7fs) (rs63749819)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506769 SCV000603925 pathogenic not specified 2018-07-05 criteria provided, single submitter clinical testing The HBB c.20delA; p.Glu7fs variant (also known as Glu6fs when numbered from the mature protein or as Codon 6 (-A), rs63749819) has been reported in multiple individuals with beta(0) thalassemia (Bouhass 1990, Gonzalez-Redondo 1988, Kazazian 1983, Rosatelli 1992, HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.002% (4/251184 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, 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 6 (-A): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=784 Bouhass R et al. A new mutation at IVS1 nt 2(T----A), in beta-thalassemia from Algeria. Blood. 1990; 76(5):1054-5. Kazazian HH Jr et al. beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene. Am J Hum Genet. 1983; 35(5):1028-33. Gonzalez-Redondo J et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. Rosatelli M et al. Molecular characterization of beta-thalassemia in the Sardinian population. Am J Hum Genet. 1992; 50(2):422-6.
Integrated Genetics/Laboratory Corporation of America RCV000576555 SCV000697093 pathogenic beta Thalassemia 2016-07-20 criteria provided, single submitter clinical testing Variant summary: The HBB c.20delA (p.Glu7Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. In addition, this region is known to be a mutational hot-spot. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.27dupG, c.36delT, c.46delT, etc.). This variant was found in 3/121348 control chromosomes at a frequency of 0.0000247, which is lower than the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is a known common pathogenic variant mainly reported in Algerian, Moroccan, and Sardinian populations in homozygous and/or heterozygous state. Additionally, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as a Pathogenic.
Baylor Genetics RCV001004359 SCV001163296 pathogenic Hb SS disease criteria provided, single submitter clinical testing
GeneDx RCV001008068 SCV001167805 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The c.20delA variant in the HBB gene has been reported previously in association with beta-thalassemia (Kazazian et al., 1983; Lazarin et al., 2013). The c.20delA variant causes a frameshift starting with codon Glutamic Acid 7, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Glu7GlyfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.20delA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.20delA as a pathogenic variant, which is likely associated with thalassemia minor. This variant has been confirmed to be seen paternally inherited.
OMIM RCV000016674 SCV000036944 pathogenic beta^0^ Thalassemia 1993-12-01 no assertion criteria provided literature only
Counsyl RCV000576555 SCV000677937 pathogenic beta Thalassemia 2015-11-24 no assertion criteria provided clinical testing

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