ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.135del (p.Phe46fs) (rs80356820)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169145 SCV000220366 pathogenic beta Thalassemia 2014-05-31 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507725 SCV000601242 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506501 SCV000603916 pathogenic not specified 2018-07-03 criteria provided, single submitter clinical testing The Codon 44 (-C) variant (HBB: c.135delC; p.Phe46fs, also known as Phe45fs when numbered from the mature protein; rs80356820) is described in the literature in the homozygous and trans-heterozygous state in individuals affected with beta thalassemia (Jalilian 2017, HbVar and references therein). It has also been reported in the heterozygous state in individuals affected with mild microcytic anemia (De Angioletti 2013, Han 2016, HbVar and references therein). This variant is found on only four chromosomes (4/251414 alleles) in the Genome Aggregation Database and is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15415). 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, the c.135delC variant is considered to be pathogenic. References: Link to variant in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=854 De Angioletti M et al. (2013) South-Italy beta-thalassemia: a novel deletion not removing the ?-globin silencing element and with 3' breakpoint in a hsRTVL-H element, associated with beta-thalassemia and high levels of HbF. Haematologica. 98(8):e98-e100. Han L et al. Molecular Epidemiological Survey of Glucose-6-Phosphate Dehydrogenase Deficiency and Thalassemia in Uygur and Kazak Ethnic Groups in Xinjiang, Northwest China. Hemoglobin. 2016 Jun;40(3):179-86. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64.
Integrated Genetics/Laboratory Corporation of America RCV000169145 SCV000697078 pathogenic beta Thalassemia 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The HBB c.135delC (p.Phe46Leufs) 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.143_146dupATCT (p.Thr51fs)). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121382 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in numerous BTHAL patients and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant has been indicated to be a common BTHAL mutation in Middle Eastern individuals. Taken together, this variant is classified as pathogenic.
OMIM RCV000016671 SCV000036941 pathogenic beta^0^ Thalassemia 1982-09-25 no assertion criteria provided literature only
GeneReviews RCV000169145 SCV000040705 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000169145 SCV001244551 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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