ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.380T>G (p.Val127Gly)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.380T>G (p.Val127Gly)
Variation ID: 15483 Accession: VCV000015483.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225662 (GRCh38) [ NCBI UCSC ] 11: 5246892 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 26, 2018 Feb 20, 2024 Nov 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.380T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Val127Gly missense NC_000011.10:g.5225662A>C NC_000011.9:g.5246892A>C NG_000007.3:g.71954T>G NG_046672.1:g.3597A>C NG_053049.1:g.1983A>C NG_059281.1:g.6410T>G LRG_1232:g.6410T>G LRG_1232t1:c.380T>G LRG_1232p1:p.Val127Gly P68871:p.Val127Gly - Protein change
- V127G
- Other names
- V126G
- Hb Dhonburi
- Hb Neapolis
- CD 126 GTG>GGG
- Canonical SPDI
- NC_000011.10:5225661:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HBB | - | - |
GRCh38 GRCh37 |
21 | 1818 | |
LOC107133510 | - | - | - | GRCh38 | - | 1770 |
LOC110006319 | - | - | - | GRCh38 | - | 977 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2004 | RCV000016741.15 | |
Pathogenic (2) |
criteria provided, single submitter
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Apr 18, 2018 | RCV000674175.13 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2023 | RCV000756239.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2021 | RCV001260263.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000799463.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Nov 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883987.3
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134231.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Beta thalassemia intermedia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361819.3
First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002233194.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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, … (more)
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). (less)
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Pathogenic
(Jan 01, 2004)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN DHONBURI
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037011.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 26, 2018 |
Comment on evidence:
While investigating the mechanism of a beta-thalassemia intermedia phenotype in a 34-year-old Thai male, Bardakdjian-Michau et al. (1990) discovered a new beta-hemoglobin variant, val126-to-gly, which … (more)
While investigating the mechanism of a beta-thalassemia intermedia phenotype in a 34-year-old Thai male, Bardakdjian-Michau et al. (1990) discovered a new beta-hemoglobin variant, val126-to-gly, which they called Hb Dhonburi. The variant was unstable but exhibited normal oxygen-binding properties. Pagano et al. (1991) found the same amino acid substitution in 3 unrelated families from southern Italy and dubbed it Neapolis. A GTG-to-GGG mutation was responsible for the change. The 8 heterozygous patients showed hematologic and biosynthetic alterations of mild beta-thalassemia. The characteristics were very similar to those of Hb E (141900.0071), Hb Knossos (141900.0149), and Hb Malay (141900.0168), all of which have a single base substitution causing amino acid replacement and alternative splicing of the precursor beta-mRNA by activating cryptic donor sites in exon 1. Moghimi et al. (2004) demonstrated this variant in a family from northern Iran. (less)
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Pathogenic
(Nov 25, 2019)
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no assertion criteria provided
Method: curation
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244568.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Molecular characteristics of thalassemia and hemoglobin variants in prenatal diagnosis program in northern Thailand. | Mankhemthong K | International journal of hematology | 2019 | PMID: 31240559 |
Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China. | He J | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125089 |
Problems in determining thalassemia carrier status in a program for prevention and control of severe thalassemia syndromes: a lesson from Thailand. | Viprakasit V | Clinical chemistry and laboratory medicine | 2013 | PMID: 23525874 |
Simple, efficient, and cost-effective multiplex genotyping with matrix assisted laser desorption/ionization time-of-flight mass spectrometry of hemoglobin beta gene mutations. | Thongnoppakhun W | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19460936 |
Multicenter study of the molecular basis of thalassemia intermedia in different ethnic populations. | Verma IC | Hemoglobin | 2007 | PMID: 17994378 |
Neapolis (CD 126 beta+ GGT->GGG): a result of a screening in Campania, a region in Southern Italy. | Pagano L | Haematologica | 2007 | PMID: 17606453 |
Two independent origins of Hb Dhonburi (Neapolis) [beta 126 (H4) Val-->Gly]: an electrophoretically silent hemoglobin variant. | Viprakasit V | Clinica chimica acta; international journal of clinical chemistry | 2007 | PMID: 17007829 |
Hb Dhonburi (Neapolis) [beta126(H4)Val-->Gly] identified in a family from northern Iran. | Moghimi B | Hemoglobin | 2004 | PMID: 15658193 |
A rare case of compound heterozygosity for delta(+)27 and Hb Neapolis (Dhonburi) associated to an atypical beta-thalassemia phenotype. | Grosso M | Haematologica | 2001 | PMID: 11532628 |
Compound heterozygosity for Hb Lepore-Boston and Hb Neapolis (Dhonburi) [beta 126(H4)Val-->Gly] in a patient from Naples, Italy. | Pagano L | Hemoglobin | 1997 | PMID: 9028819 |
Genetic heterogeneity of beta-thalassemia in southeast Sicily. | Schilirò G | American journal of hematology | 1995 | PMID: 7530406 |
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. | Divoky V | Biochimica et biophysica acta | 1992 | PMID: 1463768 |
Hemoglobin Neapolis, beta 126(H4)Val----Gly: a novel beta-chain variant associated with a mild beta-thalassemia phenotype and displaying anomalous stability features. | Pagano L | Blood | 1991 | PMID: 1954392 |
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. | Bardakdjian-Michau J | American journal of hematology | 1990 | PMID: 2399911 |
https://ithanet.eu/db/ithagenes?ithaID=1235 | - | - | - | - |
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Text-mined citations for rs33925391 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.