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 RCV001282387 SCV000883987 likely pathogenic none provided 2020-03-02 criteria provided, single submitter clinical testing The Hb Dhonburi (Neapolis) variant (HBB: c.380T>G; p.Val127Gly, also known as Val126Gly when numbered from the mature protein, rs33925391) has been reported in the heterozygous state in individuals with mild microcytosis and hypochromia (see HbVar link, Divoky 1992, Moghimi 2004). This variant is reported in ClinVar (Variation ID: 15483), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Hb Dhonburi is electrophoretically silent, but is reported to be mildly unstable in non-physiologic conditions (Bardakdjian-Michau 1990, Pagano 1991). This variant 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, the Hb Dhonburi 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. Pagano L et al. Hemoglobin Neapolis, beta 126(H4)Val----Gly: a novel beta-chain variant associated with a mild beta-thalassemia phenotype and displaying anomalous stability features. Blood. 1991 Dec 1;78(11):3070-5.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260263 SCV001361819 pathogenic Beta thalassemia intermedia 2020-09-11 criteria provided, single submitter clinical testing Variant summary: HBB c.380T>G (p.Val127Gly; 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, Mankhemthong_2019). 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). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and 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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