ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.380T>G (p.Val127Gly) (rs33925391)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674175 SCV000799463 pathogenic beta Thalassemia 2018-04-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756239 SCV000883987 likely pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The Hb Dhonburi (Neapolis) variant (HBB: c.380T>G; Val126Gly) (rs33925391) has been reported in the heterozygous state in individuals with mild microcytosis and hypochromia (see HbVar link, Divoky 1992, Moghimi 2004). It is reported in ClinVar (Variation ID: 15483) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Hb Dhonburi is reported to be mildly unstable and has been associated with a mild beta thalassemia phenotype with variable clinical presentation when in combination with a beta(0) HBB variant on the opposite chromosome (Bardakdjian-Michau 1990). However, an individual from the same family who was compound heterozygous for Hb E/Hb Dhonburi had hematological findings that could be explained by Hb E alone. Based on available information, this variant is likely to be a mildly unstable structural variant and is considered likely pathogenic. References: HbVar link: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=521 Bardakdjian-Michau J et al. Hemoglobin Dhonburi alpha 2 beta 2 126 (H4) Val----Gly: a new unstable beta variant producing a beta-thalassemia intermedia phenotype in association with beta zero-thalassemia. Am J Hematol. 1990 Oct;35(2):96-9. Divoky V et al. Heterozygosity for the IVS-I-5 (G-->C) mutation with a G-->A change at codon 18 (Val-->Met; Hb Baden) in cis and a T-->G mutation at codon 126 (Val-->Gly; Hb Dhonburi) in trans resulting in a thalassemia intermedia. Biochim Biophys Acta. 1992 Dec 10;1180(2):173-9. Moghimi B et al. Hb Dhonburi (Neapolis) [beta126(H4)Val-->Gly] identified in a family from northern Iran. Hemoglobin. 2004;28(4):353-6.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000756239 SCV001134231 pathogenic not provided 2019-01-28 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Integrated Genetics/Laboratory Corporation of America RCV000674175 SCV001361819 pathogenic beta Thalassemia 2019-06-05 criteria provided, single submitter clinical testing Variant summary: HBB c.380T>G (p.Val127Gly; aka Hb Dhonburi or Hb Neapolis) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251316 control chromosomes (gnomAD); however it was detected in several clinically silent carriers in Italy and certain parts of Asia (Pagano_1991, Pagano_2007, Moghimi_2004, Viprakasit_2007, He_2017). c.380T>G has been reported in the literature in multiple compound heterozygous individuals affected with Beta Thalassemia Intermedia, who also carried another HBB disease variant (usually for beta0 or severe beta+ thalassemia) in trans (e.g. Bardakdjian-Michau_1990, Divoky_1992, Pagano_2007). Compound heterozygous individuals who carried the variant of interest with the HbE variant (c.79G>A/p.Glu27Lys) in trans, were either reported as clinically silent (Bardakdjian-Michau_1990), or affected only with a mild beta thalassemia intermedia (Viprakasit_2007). The variant was also reported in a patient, who carried the Hb Lepore-Boston variant and was affected with a mild thalassemia intermedia (Pagano_1997). These data indicate that the variant is very likely to be associated with disease. The variant protein was demonstrated to be unstable under certain in vitro conditions (Pagano_1991, Divoky_1992). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000016741 SCV000037011 pathogenic Hemoglobinopathy 2004-01-01 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000674175 SCV001244568 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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