ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.203_204del (p.Val68fs) (rs34282684)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029968 SCV000052623 likely pathogenic Beta thalassemia major 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508401 SCV000601257 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590298 SCV000697091 likely pathogenic beta Thalassemia 2016-04-12 criteria provided, single submitter clinical testing Variant Summary: Variant causes deletion of two adjacent conserved nucleotides and results in a frameshift in 147 amino acids long HBB at position 68 and stop codon 4 amino acids downstream. The deletion is absent in the broad and large cohorts of the ExAC project. One beta-thalasssemia major patient is reported in the literature to have the variant in compound heterozygosity with a complete beta-globin gene (Eng_HumMutat_1993). In vivo/vitro studies to describe the functional impact of the variant were not reported in the literature and classification of the variant by independent clinical diagnostic centers is not available at the time of scoring. Considering the available evidences, the variant was classified as likely pathogenic until more evidence becomes available.
Invitae RCV000508401 SCV000949031 pathogenic not provided 2018-11-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val68Alafs*5) 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 on the opposite chromosome (in trans) from other pathogenic variant in an individual affected with beta thalassemia (PMID: 8257991). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 36303). Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000917 SCV001158004 pathogenic not specified 2018-11-14 criteria provided, single submitter clinical testing The HBB c.203_204delTG; p.Val68fs variant (rs34282684), also known as Codon 67 (-TG), is reported in the literature in an individual with beta-thalassemia major in trans to a whole-gene HBB deletion (Eng 1993). The c.203_204delTG variant was also observed in heterozygous relatives with hematological profiles consistent with beta-thalassemia minor (Eng 1993). This variant is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 36303). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two 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 HbVar database entry: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=868 Eng B et al. Identification of two novel beta zero-thalassemia mutations in a Filipino family: frameshift codon 67 (-TG) and a beta-globin gene deletion. Hum Mutat. 1993;2(5):375-9.
Counsyl RCV000590298 SCV001132414 likely pathogenic beta Thalassemia 2015-11-16 no assertion criteria provided clinical testing

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