ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.93G>T (p.Arg31Ser)
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.93G>T (p.Arg31Ser)
Variation ID: 15368 Accession: VCV000015368.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226799 (GRCh38) [ NCBI UCSC ] 11: 5248029 (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 May 9, 2018 Jan 6, 2024 Jun 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.93G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Arg31Ser missense NC_000011.10:g.5226799C>A NC_000011.9:g.5248029C>A NG_000007.3:g.70817G>T NG_042296.1:g.330C>A NG_046672.1:g.4734C>A NG_059281.1:g.5273G>T LRG_1232:g.5273G>T LRG_1232t1:c.93G>T LRG_1232p1:p.Arg31Ser - Protein change
- R31S
- Other names
- R30S
- Hb Tacoma
- Canonical SPDI
- NC_000011.10:5226798:C:A
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00028
The Genome Aggregation Database (gnomAD), exomes 0.00035
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
20 | 1819 | |
LOC106099062 | - | - | - | GRCh38 | - | 853 |
LOC107133510 | - | - | - | GRCh38 | - | 1772 |
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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Uncertain significance (2) |
criteria provided, single submitter
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Nov 11, 2019 | RCV000016619.17 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 1, 2002 | RCV000016620.37 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2023 | RCV000985758.21 | |
Uncertain significance (1) |
no assertion criteria provided
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Mar 16, 2021 | RCV001831573.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 26, 2021 | RCV002288497.9 |
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
Help
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
Help
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
(Nov 11, 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: SCV001363913.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HBB c.93G>T (p.Arg31Ser, also known as Hb Tacoma) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the … (more)
Variant summary: HBB c.93G>T (p.Arg31Ser, also known as Hb Tacoma) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00035 in 251316 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (0.00035 vs 0.011), allowing no conclusion about variant significance. Hb Tacoma is used to describe the substitution of Arg-to-Ser at codon 31 (legacy codon 30) and can be due to either c.93G>T or c.93G>C. It has been reported in the literature in heterozygous individuals with no clinical or hematological abnormalities apart from mild anemia (Deacon-Smith_1978, Harano_1985) and in one heterozygous individual who also carried Hb S and had normal hematological findings (Honig_1980). c.93G>T in particular was reported in heterozygous individuals with normal hematological findings in some of them and slight hemolytic anemia in others, while importantly it was also reported in a 12-year-old boy in compound heterozygosity with pathogenic variant c.93-21G>A and no signs of disease (Landin 1993, 2000). These reports do not provide unequivocal conclusions about association of the variant with Beta Thalassemia. Experimental evidence evaluating an impact on protein function demonstrate the variant to display in vitro instability, including a decreased alkaline Bohr effect and haem--haem interaction but normal oxygen affinity (Deacon-Smith_1978, Hayashi_1974). These data do not allow convincing conclusions about the variant effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Nov 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580491.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PP3, BP2
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Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Jun 21, 2018)
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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: SCV003516795.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine with serine at codon 31 of the HBB protein (p.Arg31Ser). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with serine at codon 31 of the HBB protein (p.Arg31Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs1135071, ExAC 0.3%). This variant has been observed in individuals and families with elevated Hb A2 levels, but most individuals are either clinically unaffected or experience only mild anemia (PMID: 8226093, 4525423, 5869485, 3937827, 7357091). This variant is also known as Arg30Ser and Hb Tacoma in the literature. ClinVar contains an entry for this variant (Variation ID: 15368). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 18, 2023)
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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: SCV001134242.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
The HBB c.93G>T (p.Arg31Ser) variant (also known as Hb Tacoma) has been reported to have normal oxygen affinity but slightly reduced stability (PMIDs: 31553106 (2020), … (more)
The HBB c.93G>T (p.Arg31Ser) variant (also known as Hb Tacoma) has been reported to have normal oxygen affinity but slightly reduced stability (PMIDs: 31553106 (2020), 7357091 (1980), 5785231 (1969), 5869485 (1965)). Individuals who are heterozygous for this variant have normal presentations (PMID: 5869485 (1965)) or mild anemia (PMIDs: 34233561 (2021), 8226093 (1993), 3937827 (1985)). Co-occurrence of this variant with Hb S presented as clinically healthy (PMID: 7357091 (1980)), but in combination with a beta(+)-thalassemia variant resulted in moderate microcytic anemia (PMID: 10975446 (2000)). Additionally, an individual who was compound heterozygous for Hb Tacoma caused by a different nucleotide change (c.93G>C, p.Arg31Ser) and a HBB pathogenic variant associated with beta(0)-thalassemia is reported to have transfusion-dependent beta thalassemia (PMID: 9140720 (1997)). Analysis of this variant using bioinformatics tools indicates that the effect of this variant's amino acid change on protein structure and function is damaging, and it may also affect proper HBB mRNA splicing. Clinical correlation and genetic counseling are recommended. (less)
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Uncertain significance
(Mar 02, 2022)
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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: SCV002049580.5
First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023 |
Comment:
The Hb Tacoma variant (HBB: c.93G>T; p.Arg31Ser, also known as Arg30Ser when numbered from the mature protein, HbVar ID: 289, rs1135071) is reported in the … (more)
The Hb Tacoma variant (HBB: c.93G>T; p.Arg31Ser, also known as Arg30Ser when numbered from the mature protein, HbVar ID: 289, rs1135071) is reported in the literature in the heterozygous state in individuals with mild anemia or no symptoms (Deacon-Smith 1978, Idelson 1974, Landin 1993), and in one individual with Hb S who had sickle cell trait (Honig 1980). This variant is also reported in ClinVar (Variation ID: 15368) and is found in the Finnish European population with an allele frequency of 0.36% (90/25120 alleles) in the Genome Aggregation Database. The arginine at codon 31 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.947). This variant is the first nucleotide of the exon, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Functional analyses demonstrate a normal oxygen affinity but slight instability (Deacon-Smith 1978, Honig 1980). Due to conflicting information, the clinical significance of the Hb Tacoma variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Deacon-Smith RA and Lee-Potter JP. An unstable haemoglobin, Hb Tacoma beta30 (B12) arg leads to ser, detected at birth by the demonstration of red cell inclusions. J Clin Pathol. 1978 Sep;31(9):883-7. PMID: 711920. Honig GR et al. Two new sickle cell syndromes: HbS, Hb Camden, and alpha-thalassemia; and HbS in combination with Hb Tacoma. Blood. 1980 Apr;55(4):655-60. PMID: 7357091. Idelson LI et al. New unstable haemoglobin (Hb Moscva, beta24 (B4) Gly leads to Asp) found in the USSR. Nature. 1974 Jun 21;249(459):768-70. PMID: 4525423. Landin B and Jeppsson JO. Rare beta chain hemoglobin variants found in Swedish patients during HBA1c analysis. Hemoglobin. 1993 Aug;17(4):303-18. PMID: 8226093. (less)
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Pathogenic
(Feb 01, 2002)
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no assertion criteria provided
Method: literature only
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HEINZ BODY HEMOLYTIC ANEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036889.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
See Baur and Motulsky (1965), Brimhall et al. (1969), Idelson et al. (1974), Deacon-Smith and Lee-Potter (1978), and Harano et al. (1985).
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Uncertain significance
(Mar 16, 2021)
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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: SCV002089231.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Pathogenic
(Feb 01, 2002)
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Flagged submission
flagged submission
Method: literature only
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000036888 appears to be redundant with SCV000036889.
(less)
Notes: SCV000036888 appears to
(...more)
Source: NCBI
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HEMOGLOBIN TACOMA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036888.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
See Baur and Motulsky (1965), Brimhall et al. (1969), Idelson et al. (1974), Deacon-Smith and Lee-Potter (1978), and Harano et al. (1985).
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Hb Tacoma: G>T or G>C, and Does It Matter? | Moore JA | Hemoglobin | 2021 | PMID: 34233561 |
Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. | Scheps KG | Human mutation | 2020 | PMID: 31553106 |
Investigation of mutations in the HBB gene using the 1,000 genomes database. | Carlice-Dos-Reis T | PloS one | 2017 | PMID: 28379995 |
Improvements in phenotype studies of hemoglobin disorders brought by advances in reversed-phase chromatography of globin chains. | Riou J | International journal of laboratory hematology | 2015 | PMID: 25130136 |
Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
Hb A2-Monreale [delta146(HC3)His-->Arg], a novel delta chain variant detected in west Sicily. | De Angioletti M | Hemoglobin | 2002 | PMID: 11939506 |
Compound heterozygosity for Hb Tacoma [beta30(B12)Arg-->Ser] and beta+-thalassemia. | Landin B | Hemoglobin | 2000 | PMID: 10975446 |
A significant beta-thalassemia heterogeneity in the United Arab Emirates. | el-Kalla S | Hemoglobin | 1997 | PMID: 9140720 |
Rare beta chain hemoglobin variants found in Swedish patients during HBA1c analysis. | Landin B | Hemoglobin | 1993 | PMID: 8226093 |
Hb Tacoma [beta 30(B12) Arg----Ser], a slightly unstable hemoglobin variant found in Japan. | Harano K | Hemoglobin | 1985 | PMID: 3937827 |
Percentages of abnormal hemoglobins in adults with a heterozygosity for an alpha-chain and/or a beta-chain variant. | Huisman TH | American journal of hematology | 1983 | PMID: 6859036 |
Two new sickle cell syndromes: HbS, Hb Camden, and alpha-thalassemia; and HbS in combination with Hb Tacoma. | Honig GR | Blood | 1980 | PMID: 7357091 |
An unstable haemoglobin, Hb Tacoma beta30 (B12) arg leads to ser, detected at birth by the demonstration of red cell inclusions. | Deacon-Smith RA | Journal of clinical pathology | 1978 | PMID: 711920 |
New unstable haemoglobin (Hb Moscva, beta24 (B4) Gly leads to Asp) found in the USSR. | Idelson LI | Nature | 1974 | PMID: 4525423 |
Electrophoretic and functional abnormalities of haemoglobin Tacoma beta30(B12) Arg leads to Ser. | Hayashi A | Biochimica et biophysica acta | 1974 | PMID: 4407364 |
Structural characterization of hemoglobin Tacoma. | Brimhall B | Biochemistry | 1969 | PMID: 5785231 |
Hemoglobin tacoma--a beta-chain variant associated with increased hb A2. | Baur EW | Humangenetik | 1965 | PMID: 5869485 |
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Text-mined citations for rs1135071 ...
HelpRecord last updated May 19, 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.