ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.126_129delCTTT (p.Phe42fs) (rs80356821)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508554 SCV000601240 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000508554 SCV000610030 pathogenic not provided 2017-03-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000020328 SCV000697076 pathogenic beta Thalassemia 2016-04-12 criteria provided, single submitter clinical testing Variant summary: The c.126_129delCTTT variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.135delC, c.143_146dupATCT). Mutation taster predicts damaging outcome for this variant. This variant is found in 33/121370 control chromosomes at a frequency of 0.0002719, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant is reported in the literatures as a well-known pathogenic variant predominantly identified in East and South Asian. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
GeneDx RCV000508554 SCV000748427 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing The c.126_129delCTTT variant in the HBB gene has been reported previously in the homozygous state or with a second HBB variant in multiple individuals with beta-thalassemia (Laosombat et al., 2001; Chen et. al 2010). The c.126_129delCTTT variant causes a frameshift starting with codon Phenylalanine 42, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Phe42LeufsX19. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.126_129delCTTT variant is observed in 38/18,850 (0.202%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). We interpret c.126_129delCTTT as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000020328 SCV000914517 likely pathogenic beta Thalassemia 2018-10-31 criteria provided, single submitter clinical testing The HBB c.126_129delCTTT (p.Phe42LeufsTer19) variant, also described as codon 41/42 (-CTTT) or codon 41/42 (-TTCT), results in a frameshift and is predicted to result in premature truncation of the protein. This variant is particularly prevalent in the Chinese population and is usually associated with a beta-thalassemia phenotype (Lin et al. 2014; Zhang et al. 2015; Yu et al. 2015; Origa et al 2015). Across a selection of the available literature, the p.Phe42LeufsTer19 variant has been identified in a homozygous state in one individual and in a compound heterozygous state in seven individuals, all with beta-thalassemia (Kimura et al. 1983; Hernanda et al. 2012; Huang et al. 2014; Italia et al. 2015; Rujito et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00496 in the East Asian population of the 1000 Genomes. Based on the evidence and the potential impact of frameshift variants, the p.Phe42LeufsTer19 variant is interpreted as pathogenic for beta-thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000508554 SCV000956689 pathogenic not provided 2020-01-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe42Leufs*19) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs281864900, ExAC 0.2%). This variant has been observed in the homozygous and compound heterozygous state in several individuals with HBB-related conditions (PMID: 6826539, 28635337, 25089872). ClinVar contains an entry for this variant (Variation ID: 15417). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000877 SCV001157958 pathogenic not specified 2018-10-19 criteria provided, single submitter clinical testing The HBB c.126_129delCTTT; p.Phe42fs variant (also known as Phe41fs when numbered from the mature protein or as codon 41/42-TTCT, rs80356821) has been reported in the homozygous and compound heterozygous states in individuals affected with beta-thalassemia (see link to HbVar, Kimura 1983). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15417) and is observed in the general population at an overall frequency of 0.02% (65/277122 alleles) with increased frequency in the East Asian population (0.2%) in the Genome Aggregation Database. This variant creates a frameshift by deleting 4 nucleotides, 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 for c.126_129delCTTT: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=849&.cgifields=histD Kimura A et al. Structural analysis of a beta-thalassemia gene found in Taiwan. J Biol Chem. 1983 Mar 10;258(5):2748-9.
Baylor Genetics RCV001004569 SCV001163653 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020328 SCV001194030 pathogenic beta Thalassemia 2019-12-09 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.126_129delCTTT(F42Lfs*19) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 6826539, 25000193, 6714226 and 25480500. Classification of NM_000518.4(HBB):c.126_129delCTTT(F42Lfs*19) 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.
OMIM RCV000016673 SCV000036943 pathogenic beta^0^ Thalassemia 2002-09-28 no assertion criteria provided literature only
GeneReviews RCV000020328 SCV000040704 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000020328 SCV001244545 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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