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

dbSNP: rs33925391

Total submissions: 7

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	2023-11-22	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, HbVar ID: 521) has been reported in the heterozygous state in individuals with mild microcytosis and hypochromia (see HbVar link, Divoky 1992, Khamphikham 2022, Moghimi 2004). This variant is reported in ClinVar (Variation ID: 15483). This variant is also absent from the Genome Aggregation Database (v2.1.1), 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. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.67). Based on available information, the Hb Dhonburi variant is likely to be a mildly unstable structural variant and is considered likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html 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. PMID: 2399911. 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. PMID: 1463768. Khamphikham P et al. Strong Positive Dichlorophenolindophenol Precipitation Suggests Hb Dhonburi (or Hb Neapolis) (HBB: c.380T>G) Inheritance in a Couple at Risk for Severe ß-Thalassemia. Hemoglobin. 2022 May;46(3):184-186. PMID: 35543019. Moghimi B et al. Hb Dhonburi (Neapolis) [beta126(H4)Val-->Gly] identified in a family from northern Iran. Hemoglobin. 2004;28(4):353-6. PMID: 15658193. 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. PMID: 1954392.
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	2021-12-01	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 other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000756239	SCV002233194	pathogenic	not provided	2023-01-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 15483). This variant is also known as Hb Dhonburi, Hb Neapolis and p.Val126Gly. This missense change has been observed in individual(s) with thalassemia intermedia (PMID: 1463768, 17007829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 127 of the HBB protein (p.Val127Gly).
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