ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.4G>A (p.Val2Met)
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.4G>A (p.Val2Met)
Variation ID: 15359 Accession: VCV000015359.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5227018 (GRCh38) [ NCBI UCSC ] 11: 5248248 (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 Apr 19, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.4G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Val2Met missense NC_000011.10:g.5227018C>T NC_000011.9:g.5248248C>T NG_000007.3:g.70598G>A NG_042296.1:g.549C>T NG_046672.1:g.4953C>T NG_059281.1:g.5054G>A LRG_1232:g.5054G>A LRG_1232t1:c.4G>A LRG_1232p1:p.Val2Met - Protein change
- V2M
- Other names
- HBB, NH2 EXTENSION, VAL1MET, METi RETAINED
- Canonical SPDI
- NC_000011.10:5227017:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
Help
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
Help
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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other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016609.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 19, 2019 | RCV000508674.3 | |
Conflicting interpretations of pathogenicity (2) |
no assertion criteria provided
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Sep 8, 2023 | RCV001831572.2 |
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
Help
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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Uncertain significance
(Apr 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360651.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HBB c.4G>A (p.Val2Met; also known as Hb South Florida) results in a conservative amino acid change in the encoded protein sequence. Three of … (more)
Variant summary: HBB c.4G>A (p.Val2Met; also known as Hb South Florida) results in a 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 allele was found at a frequency of 4e-06 in 251128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant is known to interfere with some methods of HbA1c determination and has been (falsely) reported in several carriers as elevated HbA1c, but without clinical evidence of any hematologic abnormality (Shah 1986, Aslanger 2013, Celebiler 2014, Canatan 2016). These data indicate that this variant does not produce any clinical symptoms in heterozygous state. According to our knowledge, only one compound heterozygous individual has been reported in the literature who carried a pathogenic variant (c.92+1G>A) for beta-0-thalassemia in trans, and presented with beta-thalassemia trait without clinical manifestations (Tan 2006, Tan 2009). Since compound heterozygosity for two pathogenic variants would result in a more severe phenotype, this report provides supportive evidence for a benign role (Tan 2009). Early reports demonstrated that the variant prevents the cleavage of the initiator methionine (Boissel 1985), but does not result in an unstable hemoglobin (Shah 1986). However, to our knowledge no other studies performed further functional characterization, thus allowing no convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Mar 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000605844.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN SOUTH FLORIDA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036878.5
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
The initiator methionine residue (METi) is preserved. This variant was first discovered in a patient who appeared to have markedly elevated Hb A(1c) as estimated … (more)
The initiator methionine residue (METi) is preserved. This variant was first discovered in a patient who appeared to have markedly elevated Hb A(1c) as estimated by ion exchange chromatography. Glycosylated hemoglobin measured by a colorimetric method with thiobarbituric acid was normal, however. If it were not for the fact that methionine is 1 of the 4 N-terminal amino acids (alanine, glycine, serine, methionine) that participate in acetylation, this abnormal amino acid substitution would have gone unrecognized. Acetylation of the N-terminal methionine residue occurs less easily than in other amino acids; thus, hemoglobin South Florida could not be recognized by hemoglobin electrophoresis. In contrast, acetylation of alanine in hemoglobin Raleigh is 100% and that variant can be recognized by hemoglobin electrophoresis. See Boissel et al. (1985) and Shah et al. (1986). Malone et al. (1987) reported a family study. The fundamental change is not in the codon for the initiator mutation but in the codon for the first residue for the mature beta-globin chain, valine, which is converted to methionine. Because the initiator methionine is retained, this methionine is substituted for valine as residue 2 in the mature chain of Hb South Florida. (less)
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Uncertain significance
(Aug 19, 2020)
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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: SCV002091621.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Likely benign
(Sep 08, 2023)
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no assertion criteria provided
Method: clinical testing
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beta Thalassemia
Affected status: no
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV004244271.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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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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Report on Ten Years' Experience of Premarital Hemoglobinopathy Screening at a Center in Antalya, Southern Turkey. | Canatan D | Hemoglobin | 2016 | PMID: 27207683 |
Ten Years of Routine α- and β-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations. | Henderson SJ | Hemoglobin | 2016 | PMID: 26635043 |
First Observation of Hb South Florida [beta 1(NA1) Val>Met] in Turkey. | Aslanger AD | Turkish journal of haematology : official journal of Turkish Society of Haematology | 2013 | PMID: 24385794 |
Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
Interaction of Hb South Florida (codon 1; GTG-->ATG) and HbE, with beta-thalassemia (IVS1-1; G-->A): expression of different clinical phenotypes. | Tan JA | European journal of pediatrics | 2009 | PMID: 19034506 |
Characterisation and confirmation of rare beta-thalassaemia mutations in the Malay, Chinese and Indian ethnic groups in Malaysia. | Tan JA | Pathology | 2006 | PMID: 17008283 |
Hemoglobin South Florida: a genetic variant with laboratory recognition of only 20% of its product. | Malone JI | American journal of medical genetics. Supplement | 1987 | PMID: 3130858 |
Hemoglobin South Florida. New variant with normal electrophoretic pattern mistaken for glycosylated hemoglobin. | Shah SC | Diabetes | 1986 | PMID: 3758492 |
Amino-terminal processing of proteins: hemoglobin South Florida, a variant with retention of initiator methionine and N alpha-acetylation. | Boissel JP | Proceedings of the National Academy of Sciences of the United States of America | 1985 | PMID: 3866233 |
Application of high--performance liquid chromatography to abnormal hemoglobin studies. Characterization of hemoglobins D in Ivory Coast and description of a new variant hb Cocody (beta 21 (B3) Asp leads to Asn). | Boissel JP | Biochimica et biophysica acta | 1981 | PMID: 6271242 |
Text-mined citations for rs33958358 ...
HelpRecord last updated Feb 14, 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.