Variant summary: HBB c.34G>A (p.Val12Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251232 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (6e-05 vs 0.011), allowing no conclusion about variant significance. c.34G>A has been reported in the literature in individuals with moderate/mild anemia or no symptom and Autism (e.g. Manca_1987, Su_1992, Brunner-Agten_2010, Xinh_2022, Fu_2022, Zhou_2022). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Co-occurrence with a pathogenic variant on the same allele has been reported in a child affected with sickle cell syndrome (HBB c.364G>A, p.Glu122Lys; Prehu_2002), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19727720, 35982160, 3623977, 11939508, 29319890, 1428944, 35023007, 35982159). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
ClinVar Genomic variation as it relates to human health
NM_000518.4(HBB):c.34G>A (p.Val12Ile)
Germline
Classification
Help
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.
(11)
Help
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.
Uncertain significance
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_000518.4(HBB):c.34G>A (p.Val12Ile)
Variation ID: 15189 Accession: VCV000015189.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.4 11: 5226988 (GRCh38) [ NCBI UCSC ] 11: 5248218 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 25, 2025 Jun 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.34G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Val12Ile missense NC_000011.10:g.5226988C>T NC_000011.9:g.5248218C>T NG_000007.3:g.70628G>A NG_042296.1:g.519C>T NG_046672.1:g.4923C>T NG_059281.1:g.5084G>A LRG_1232:g.5084G>A LRG_1232t1:c.34G>A LRG_1232p1:p.Val12Ile P68871:p.Val12Ile - Protein change
- V12I
- Other names
-
V11I
- Canonical SPDI
- NC_000011.10:5226987:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1853 | |
| LOC106099062 | - | - | - | GRCh38 | - | 871 |
| LOC107133510 | - | - | - | GRCh38 | - | 1802 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
|
HEMOGLOBIN HAMILTON
|
other (1) |
no assertion criteria provided
|
Dec 12, 2017 | RCV000016370.12 |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 30, 2024 | RCV000756241.22 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001107684.12 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001107685.12 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001107686.12 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001104053.14 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 18, 2024 | RCV005003359.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV001778655.12 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015182.4
First in ClinVar: Nov 20, 2021 Last updated: Feb 04, 2024 |
Comment:
Variant summary: HBB c.34G>A (p.Val12Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: HBB c.34G>A (p.Val12Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251232 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (6e-05 vs 0.011), allowing no conclusion about variant significance. c.34G>A has been reported in the literature in individuals with moderate/mild anemia or no symptom and Autism (e.g. Manca_1987, Su_1992, Brunner-Agten_2010, Xinh_2022, Fu_2022, Zhou_2022). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Co-occurrence with a pathogenic variant on the same allele has been reported in a child affected with sickle cell syndrome (HBB c.364G>A, p.Glu122Lys; Prehu_2002), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19727720, 35982160, 3623977, 11939508, 29319890, 1428944, 35023007, 35982159). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
|
Uncertain significance
(Apr 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601294.6
First in ClinVar: Sep 30, 2017 Last updated: Jan 19, 2025 |
Comment:
The HBB c.34G>A (p.Val12Ile) variant has been reported in the published literature in heterozygous individuals with a normal clinical presentation (PMIDs: 1428944 (1992), 19429541 (2009), … (more)
The HBB c.34G>A (p.Val12Ile) variant has been reported in the published literature in heterozygous individuals with a normal clinical presentation (PMIDs: 1428944 (1992), 19429541 (2009), 19727720 (2010)). Additionally, this variant is described as having normal stability (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)) and not damaging to protein function (PMID: 6695908 (1984)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Mar 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883990.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The Hb Hamilton variant (HBB: c.34G>A; Val11Ile) (rs33974228) is not associated with clinical symptoms in heterozygous carriers and demonstrates normal function and relative stability (see … (more)
The Hb Hamilton variant (HBB: c.34G>A; Val11Ile) (rs33974228) is not associated with clinical symptoms in heterozygous carriers and demonstrates normal function and relative stability (see HbVar database link and references therein). However, its phenotype when found with other pathogenic globin variants is unknown. Hb Hamilton does not affect the net charge and thus is not detectable by HPLC (see HbVar database link and references therein). This variant is reported in ClinVar (Variation ID: 15189) and is observed in 1:400 live births in the Sardinian population (see HbVar database link and references therein). Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar link: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=239 (less)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001260880.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary persistence of fetal hemoglobin
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001264860.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hb SS disease
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001264861.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hemoglobin E
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001264862.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Jul 26, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003235744.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine with isoleucine at codon 12 of the HBB protein (p.Val12Ile). The valine residue is weakly conserved and there is a … (more)
This sequence change replaces valine with isoleucine at codon 12 of the HBB protein (p.Val12Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs33974228, ExAC 0.01%). This variant has been observed in individuals with HBB-related conditions (PMID: 19727720) and has been observed in healthy individuals as well (PMID: 1610915, 3623977). This variant is known as Hb Hamilton in the literature. ClinVar contains an entry for this variant (Variation ID: 15189, 15596). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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. 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)
|
|
|
Uncertain significance
(Jun 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Heinz body anemia
Hereditary persistence of fetal hemoglobin Dominant beta-thalassemia Hb SS disease Malaria, susceptibility to Beta-thalassemia HBB/LCRB METHEMOGLOBINEMIA, BETA TYPE Erythrocytosis, familial, 6
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002778762.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025 |
|
|
|
other
(Dec 12, 2017)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN HAMILTON
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036638.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Manca et al. (1987) and Wong et al. (1984). Manca et al. (1992) described an easy PCR-based method for demonstration of the mutation. They … (more)
See Manca et al. (1987) and Wong et al. (1984). Manca et al. (1992) described an easy PCR-based method for demonstration of the mutation. They demonstrated the predicted G-to-A transition at codon 11 which abolishes a MaeIII restriction site. This mutation, which is rather common among Sardinians, involves one of the 5 CpG dinucleotides of the beta-globin gene. (less)
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|
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Uncertain significance
(Sep 28, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002091610.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
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Comment:
Comment:
The HBB c.34G>A (p.Val12Ile) variant has been reported in the published literature in heterozygous individuals with a normal clinical presentation (PMIDs: 1428944 (1992), 19429541 (2009), 19727720 (2010)). Additionally, this variant is described as having normal stability (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)) and not damaging to protein function (PMID: 6695908 (1984)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The Hb Hamilton variant (HBB: c.34G>A; Val11Ile) (rs33974228) is not associated with clinical symptoms in heterozygous carriers and demonstrates normal function and relative stability (see HbVar database link and references therein). However, its phenotype when found with other pathogenic globin variants is unknown. Hb Hamilton does not affect the net charge and thus is not detectable by HPLC (see HbVar database link and references therein). This variant is reported in ClinVar (Variation ID: 15189) and is observed in 1:400 live births in the Sardinian population (see HbVar database link and references therein). Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar link: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=239
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This sequence change replaces valine with isoleucine at codon 12 of the HBB protein (p.Val12Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs33974228, ExAC 0.01%). This variant has been observed in individuals with HBB-related conditions (PMID: 19727720) and has been observed in healthy individuals as well (PMID: 1610915, 3623977). This variant is known as Hb Hamilton in the literature. ClinVar contains an entry for this variant (Variation ID: 15189, 15596). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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. 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.
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. |
Comment:
Variant summary: HBB c.34G>A (p.Val12Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251232 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (6e-05 vs 0.011), allowing no conclusion about variant significance. c.34G>A has been reported in the literature in individuals with moderate/mild anemia or no symptom and Autism (e.g. Manca_1987, Su_1992, Brunner-Agten_2010, Xinh_2022, Fu_2022, Zhou_2022). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Co-occurrence with a pathogenic variant on the same allele has been reported in a child affected with sickle cell syndrome (HBB c.364G>A, p.Glu122Lys; Prehu_2002), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19727720, 35982160, 3623977, 11939508, 29319890, 1428944, 35023007, 35982159). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
The HBB c.34G>A (p.Val12Ile) variant has been reported in the published literature in heterozygous individuals with a normal clinical presentation (PMIDs: 1428944 (1992), 19429541 (2009), 19727720 (2010)). Additionally, this variant is described as having normal stability (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)) and not damaging to protein function (PMID: 6695908 (1984)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The Hb Hamilton variant (HBB: c.34G>A; Val11Ile) (rs33974228) is not associated with clinical symptoms in heterozygous carriers and demonstrates normal function and relative stability (see HbVar database link and references therein). However, its phenotype when found with other pathogenic globin variants is unknown. Hb Hamilton does not affect the net charge and thus is not detectable by HPLC (see HbVar database link and references therein). This variant is reported in ClinVar (Variation ID: 15189) and is observed in 1:400 live births in the Sardinian population (see HbVar database link and references therein). Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar link: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=239
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This sequence change replaces valine with isoleucine at codon 12 of the HBB protein (p.Val12Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs33974228, ExAC 0.01%). This variant has been observed in individuals with HBB-related conditions (PMID: 19727720) and has been observed in healthy individuals as well (PMID: 1610915, 3623977). This variant is known as Hb Hamilton in the literature. ClinVar contains an entry for this variant (Variation ID: 15189, 15596). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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. 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. | Fu JM | Nature genetics | 2022 | PMID: 35982160 |
| Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. | Zhou X | Nature genetics | 2022 | PMID: 35982159 |
| Spectrum of HBB gene mutations among 696 β-thalassemia patients and carriers in Southern Vietnam. | Xinh PT | Molecular biology reports | 2022 | PMID: 35023007 |
| [Effect of high-throughput sequencing for the prevention and control of thalassemia]. | Chen Y | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2020 | PMID: 32472543 |
| Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. | Scheps KG | Human mutation | 2020 | PMID: 31553106 |
| Two novel unstable hemoglobin variants due to in-frame deletions of key amino acids in the β-globin chain. | Scheps KG | European journal of haematology | 2018 | PMID: 29319890 |
| Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies. | Shang X | EBioMedicine | 2017 | PMID: 28865746 |
| Prevalence and genetic analysis of α-thalassemia and β-thalassemia in Chongqing area of China. | Yao XY | Gene | 2013 | PMID: 24055728 |
| Compound heterozygosity of Hb Hamilton and de novo mutated HbM Saskatoon. | Brunner-Agten S | Annals of hematology | 2010 | PMID: 19727720 |
| Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
| Hb O-Tibesti [beta121(GH4)Glu-->Lys; beta11(A8)Val-->Ile], a hemoglobin variant carrying in the same beta chain the substitutions of Hb O-Arab and Hb Hamilton, found in combination with Hb S [beta6(A3)Glu-->Val]. | Préhu C | Hemoglobin | 2002 | PMID: 11939508 |
| Identification of Hb Hamilton or beta 11(A8)Val----Ile gene by the polymerase chain reaction amplification technique. | Manca L | Biochimica et biophysica acta | 1992 | PMID: 1610915 |
| Hb H disease in association with the silent beta chain variant Hb Hamilton or alpha 2 beta 2(11)(A8)Val----Ile. | Su CW | Hemoglobin | 1992 | PMID: 1428944 |
| Hemoglobin Hamilton [beta 11(A8)Val----Ile] in Sardinia. | Manca L | Hemoglobin | 1987 | PMID: 3623977 |
| Hemoglobin Hamilton or alpha 2 beta 2 11(A8)Val leads to Ile: a silent beta-chain variant detected by Triton X-100 acid-urea polyacrylamide gel electrophoresis. | Wong SC | American journal of hematology | 1984 | PMID: 6695908 |
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Text-mined citations for rs33974228 ...
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Record last updated Feb 01, 2025
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