ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.2T>G (p.Met1Arg)
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.2T>G (p.Met1Arg)
Variation ID: 15434 Accession: VCV000015434.105
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5227020 (GRCh38) [ NCBI UCSC ] 11: 5248250 (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 Sep 30, 2017 Feb 14, 2024 Sep 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Met1Arg missense initiator codon variant NC_000011.10:g.5227020A>C NC_000011.9:g.5248250A>C NG_000007.3:g.70596T>G NG_042296.1:g.551A>C NG_046672.1:g.4955A>C NG_059281.1:g.5052T>G LRG_1232:g.5052T>G LRG_1232t1:c.2T>G LRG_1232p1:p.Met1Arg - Protein change
- M1R
- Other names
- Init CD ATG>AGG
- Canonical SPDI
- NC_000011.10:5227019: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 | 1815 | |
LOC106099062 | - | - | - | GRCh38 | - | 849 |
LOC107133510 | - | - | - | GRCh38 | - | 1767 |
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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Jun 1, 1992 | RCV000016691.35 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2023 | RCV000505904.17 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 14, 2020 | RCV000664667.14 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004361.8 |
Submissions - Germline
Classification
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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
(Oct 05, 2017)
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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: SCV000788668.2
First in ClinVar: Aug 05, 2018 Last updated: Sep 03, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hb SS disease
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163299.2
First in ClinVar: Feb 29, 2020 Last updated: Sep 03, 2023 |
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Pathogenic
(Jul 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363914.3
First in ClinVar: Jun 22, 2020 Last updated: Sep 03, 2023 |
Comment:
Variant summary: HBB c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: HBB c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Arginine is not a known alternative start codon for eukaryotes in nature; thus, translation would be predicted to start at the next Met in the HBB protein (which is at amino acid 56), causing a loss of translation of the normal N-terminus of the protein. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). c.2T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia (e.g. Lam_1990, Lee_2002, Su_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This codon is in a mutational hotspot where other changes [such as: p.M1I (c.3G>A, C, and T), p.M1L, p.M1K, p.M1T and p.M1V] at the same residue have also been found in HBB patients (source: HGMD). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 19, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603920.3
First in ClinVar: Sep 30, 2017 Last updated: Sep 03, 2023 |
Comment:
The HBB c.2T>G; p.Met1? variant (rs33941849) is reported in the literature in individuals affected with beta(0) thalassemia (HbVar database), with no detectable expression of the … (more)
The HBB c.2T>G; p.Met1? variant (rs33941849) is reported in the literature in individuals affected with beta(0) thalassemia (HbVar database), with no detectable expression of the beta globin protein in a patient possessing a beta(0) thalassemia variant on the other chromosome (Lam 1990). This variant is reported in ClinVar (Variation ID: 15434), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant ablates the canonical translation initiation codon, and is predicted to lead to an aberrant or absent protein. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.2T>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=777 Lam V et al. A new single nucleotide change at the initiation codon (ATG----AGG) identified in amplified genomic DNA of a Chinese beta-thalassemic patient. Blood. 1990 75(5):1207-8. (less)
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Pathogenic
(Oct 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601269.5
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. It has not been … (more)
This variant disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is associated with beta-zero-thalassemia and is known to be a common Chinese beta-thalassemia pathogenic variant (PMID: 2306523 (1990), 27829298 (2016), 34474730 (2021), 34293487 (2021)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Sep 01, 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: SCV003439604.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56. Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive beta thalassemia (PMID: 12955718, 14715623, 29695942). This variant has been reported in individual(s) with autosomal dominant beta thalassemia (PMID: 8144357); however, the role of the variant in this condition is currently unclear. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 15434). This variant is also known as CD0T>G, Initiation codon ATG‚ÜíAGG. (less)
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Pathogenic
(Jun 01, 1992)
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no assertion criteria provided
Method: literature only
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BETA-ZERO-THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036961.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2023 |
Comment on evidence:
This initiator codon mutant, ATG to AGG, was found in Chinese individuals by Kazazian (1990).
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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: SCV001244631.2
First in ClinVar: May 04, 2020 Last updated: Sep 03, 2023 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Beta thalassemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002091622.2
First in ClinVar: Apr 23, 2022 Last updated: Sep 03, 2023 |
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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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Sickle Cell Disease. | Adam MP | - | 2023 | PMID: 20301551 |
Effectiveness of Using Mean Corpuscular Volume and Mean Corpuscular Hemoglobin for Beta-thalassemia Carrier Screening in the Guangdong Population of China. | Gu H | Biomedical and environmental sciences : BES | 2021 | PMID: 34474730 |
A More Universal Approach to Comprehensive Analysis of Thalassemia Alleles (CATSA). | Liang Q | The Journal of molecular diagnostics : JMD | 2021 | PMID: 34293487 |
β-Hemoglobinopathies in the Lao People's Democratic Republic: Molecular diagnostics and implication for a prevention and control program. | Singha K | International journal of laboratory hematology | 2021 | PMID: 33244864 |
Genotype-phenotype correlation among beta-thalassemia and beta-thalassemia/HbE disease in Thai children: predictable clinical spectrum using genotypic analysis. | Traivaree C | Journal of blood medicine | 2018 | PMID: 29695942 |
A novel compound heterozygosity in Southern China: IVS-II-5 (G > C) and IVS-II-672 (A > C). | Zhao L | Hemoglobin | 2016 | PMID: 27829298 |
Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A). | Boucher MO | Hemoglobin | 2016 | PMID: 27117572 |
Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease. | Akinbami AO | Hemoglobin | 2016 | PMID: 26372199 |
Mutation screening for thalassaemia in the Jino ethnic minority population of Yunnan Province, Southwest China. | Wang S | BMJ open | 2015 | PMID: 26715484 |
Molecular analysis of beta-globin gene mutations among Thai beta-thalassemia children: results from a single center study. | Boonyawat B | The application of clinical genetics | 2014 | PMID: 25525381 |
Hereditary hemolytic anemia in Korea from 2007 to 2011: A study by the Korean Hereditary Hemolytic Anemia Working Party of the Korean Society of Hematology. | Park ES | Blood research | 2013 | PMID: 24086942 |
The clinical and laboratory spectrum of Hb C [β6(A3)Glu→Lys, GAG>AAG] disease. | Cook CM | Hemoglobin | 2013 | PMID: 23297836 |
Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia. | Sivalingam M | International journal of laboratory hematology | 2012 | PMID: 22335963 |
Molecular basis of β-thalassemia in the western province of Saudi Arabia: identification of rare β-thalassemia mutations. | Abuzenadah AM | Hemoglobin | 2011 | PMID: 21797702 |
Rapid identification of HBB gene mutations by high-resolution melting analysis. | Shih HC | Clinical biochemistry | 2009 | PMID: 19631632 |
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 |
Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
Variation and heritability of Hb F and F-cells among beta-thalassemia heterozygotes in Hong Kong. | Gibney GT | American journal of hematology | 2008 | PMID: 18266208 |
Evaluation of alpha hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients with beta thalassemia. | Viprakasit V | Blood | 2004 | PMID: 14715623 |
Rapid detection of beta-globin gene (HBB) mutations coupling heteroduplex and primer-extension analysis by DHPLC. | Su YN | Human mutation | 2003 | PMID: 12955718 |
RFLP haplotypes of beta-globin gene complex of beta-thalassemic chromosomes in Koreans. | Lee YJ | Journal of Korean medical science | 2002 | PMID: 12172041 |
beta-thalassemia mutations in Japanese and Koreans. | Ohba Y | Hemoglobin | 1997 | PMID: 9101288 |
Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. | Chiou SS | British journal of haematology | 1993 | PMID: 8435318 |
A novel initiation codon mutation (ATG-->ATT) in a beta-thalassemia patient. | Rahbar S | Hemoglobin | 1993 | PMID: 8144357 |
Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene. | Kazazian HH Jr | Blood | 1992 | PMID: 1586746 |
A beta-thalassemia mutation found in Korea. | Koo MS | Hemoglobin | 1992 | PMID: 1517111 |
A new single nucleotide change at the initiation codon (ATG----AGG) identified in amplified genomic DNA of a Chinese beta-thalassemic patient. | Lam VM | Blood | 1990 | PMID: 2306523 |
https://ithanet.eu/db/ithagenes?ithaID=45 | - | - | - | - |
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Text-mined citations for rs33941849 ...
HelpRecord last updated Apr 20, 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.