ClinVar Genomic variation as it relates to human health
NM_000518.4(HBB):c.332T>C (p.Leu111Pro)
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_000518.4(HBB):c.332T>C (p.Leu111Pro)
Variation ID: 15352 Accession: VCV000015352.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225710 (GRCh38) [ NCBI UCSC ] 11: 5246940 (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 Apr 4, 2013 Feb 20, 2024 May 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.332T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Leu111Pro missense NC_000011.10:g.5225710A>G NC_000011.9:g.5246940A>G NG_000007.3:g.71906T>C NG_046672.1:g.3645A>G NG_053049.1:g.2031A>G NG_059281.1:g.6362T>C LRG_1232:g.6362T>C LRG_1232t1:c.332T>C LRG_1232p1:p.Leu111Pro P68871:p.Leu111Pro - Protein change
- L111P
- Other names
- L110P
- Canonical SPDI
- NC_000011.10:5225709:A:G
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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
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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
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. |
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HBB | - | - |
GRCh38 GRCh37 |
21 | 1815 | |
LOC107133510 | - | - | - | GRCh38 | - | 1765 |
LOC110006319 | - | - | - | GRCh38 | - | 975 |
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. |
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other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016598.12 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2005 | RCV000016599.36 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2005 | RCV000016600.36 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 26, 2016 | RCV000589517.11 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004561.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV002476975.12 |
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. |
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Pathogenic
(May 22, 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: SCV002774347.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
Comment:
The HBB c.332T>C (p.Leu111Pro) pathogenic variant (also known as Hb Showa-Yakushiji) is reported in the published literature as a hyper unstable variant associated with beta … (more)
The HBB c.332T>C (p.Leu111Pro) pathogenic variant (also known as Hb Showa-Yakushiji) is reported in the published literature as a hyper unstable variant associated with beta thalassemia major and intermedia (PMIDs: 28670940 (2017), 27263053 (2016), 18495504 (2008), 15768552 (2005), 2634667 (1989), 2822177 (1987)). 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 damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158588.4
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The Hb Showa-Yakushiji variant (HBB: c.332T>C; p.Leu111Pro, also known as Leu110Pro when numbered from the mature protein, rs35256489, HbVar ID: 485) is reported to be … (more)
The Hb Showa-Yakushiji variant (HBB: c.332T>C; p.Leu111Pro, also known as Leu110Pro when numbered from the mature protein, rs35256489, HbVar ID: 485) is reported to be a hyperunstable hemoglobin associated with beta(+) thalassemia (Colah 2008, Edison 2005, Kobayashi 1987, HbVar link). This variant is reported as pathogenic in ClinVar (Variation ID: 15352). It is only observed in one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 111 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.871). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Colah R et al. Hb Showa Yakushiji (beta 110 (G12) Leu-->Pro) in 3 families from Western India: first report on homozygous Hb Showa Yakushiji. Blood Cells Mol Dis. 2008 Sep-Oct;41(2):166-8. PMID: 18495504. Edison ES et al. Hb Showa-Yakushiji (beta110(G12)Leu-->Pro) in four unrelated patients from west Bengal. Hemoglobin. 2005;29(1):19-25. PMID: 15768552. Kobayashi Y et al. A novel globin structural mutant, Showa-Yakushiji (beta 110 Leu-Pro) causing a beta-thalassemia phenotype. Blood. 1987 Nov;70(5):1688-91. PMID: 2822177. (less)
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Pathogenic
(Aug 26, 2016)
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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: SCV000697122.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The HBB c.332T>C (p.Leu111Pro) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to … (more)
Variant summary: The HBB c.332T>C (p.Leu111Pro) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121382, which does not exceed the estimated maximal expected allele frequency for a pathogenic HBB variant of 1/89. The variant of interest has been reported in multiple affected individuals in both homozygous and compound heterozygous states. In addition, a reputable database cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. (less)
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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: SCV001163645.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Jan 01, 2005)
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no assertion criteria provided
Method: literature only
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BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036868.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988) described a novel HBB mutation that produced the beta-thalassemia phenotype (613985) through … (more)
In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988) described a novel HBB mutation that produced the beta-thalassemia phenotype (613985) through a posttranslational mechanism. Substitution of proline for leucine at position 110 greatly reduced the molecular stability of the beta-globin subunit, leading to total destruction of the variant globin chains by proteolysis. The mutation could be identified after digestion with the restriction enzyme MspI. They named the variant Hb Showa-Yakushiji, after the 2 districts where the probands resided. Other variant hemoglobins that are very unstable and lead to thalassemia include Hb Indianapolis (141900.0117) and Hb Quong Sze (141900.0005). In 4 unrelated individuals in India, Edison et al. (2005) found the hyper-unstable variant Hb Showa-Yakushiji in compound heterozygosity with other mutations producing beta-thalassemia or with Hb E (141900.0071). In all 4 patients, the mutation was found on the same haplotype, which differed from the Japanese haplotype, indicating its independent origin in India. (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN SHOWA-YAKUSHIJI
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036867.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988) described a novel HBB mutation that produced the beta-thalassemia phenotype (613985) through … (more)
In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988) described a novel HBB mutation that produced the beta-thalassemia phenotype (613985) through a posttranslational mechanism. Substitution of proline for leucine at position 110 greatly reduced the molecular stability of the beta-globin subunit, leading to total destruction of the variant globin chains by proteolysis. The mutation could be identified after digestion with the restriction enzyme MspI. They named the variant Hb Showa-Yakushiji, after the 2 districts where the probands resided. Other variant hemoglobins that are very unstable and lead to thalassemia include Hb Indianapolis (141900.0117) and Hb Quong Sze (141900.0005). In 4 unrelated individuals in India, Edison et al. (2005) found the hyper-unstable variant Hb Showa-Yakushiji in compound heterozygosity with other mutations producing beta-thalassemia or with Hb E (141900.0071). In all 4 patients, the mutation was found on the same haplotype, which differed from the Japanese haplotype, indicating its independent origin in India. (less)
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Pathogenic
(Jan 01, 2005)
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no assertion criteria provided
Method: literature only
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BETA-SHOWA-YAKUSHIJI THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036869.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988) described a novel HBB mutation that produced the beta-thalassemia phenotype (613985) through … (more)
In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988) described a novel HBB mutation that produced the beta-thalassemia phenotype (613985) through a posttranslational mechanism. Substitution of proline for leucine at position 110 greatly reduced the molecular stability of the beta-globin subunit, leading to total destruction of the variant globin chains by proteolysis. The mutation could be identified after digestion with the restriction enzyme MspI. They named the variant Hb Showa-Yakushiji, after the 2 districts where the probands resided. Other variant hemoglobins that are very unstable and lead to thalassemia include Hb Indianapolis (141900.0117) and Hb Quong Sze (141900.0005). In 4 unrelated individuals in India, Edison et al. (2005) found the hyper-unstable variant Hb Showa-Yakushiji in compound heterozygosity with other mutations producing beta-thalassemia or with Hb E (141900.0071). In all 4 patients, the mutation was found on the same haplotype, which differed from the Japanese haplotype, indicating its independent origin in India. (less)
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Pathogenic
(Sep 16, 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: SCV002089188.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Rare β-Globin Gene Mutations in Pakistan. | Hussain A | Hemoglobin | 2017 | PMID: 28670940 |
The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. | Yasmeen H | European journal of medical genetics | 2016 | PMID: 27263053 |
Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. | Sinha S | The HUGO journal | 2009 | PMID: 21119755 |
Regional heterogeneity of beta-thalassemia mutations in the multi ethnic Indian population. | Colah R | Blood cells, molecules & diseases | 2009 | PMID: 19254853 |
Hb Showa Yakushiji [beta 110 (G12) Leu-->Pro] in 3 families from Western India: first report on homozygous Hb Showa Yakushiji. | Colah R | Blood cells, molecules & diseases | 2008 | PMID: 18495504 |
The rare Hb Showa-Yakushiji [beta110(G12)Leu-->Pro, CTG-->CCG] in combination with an alpha gene triplication found in a Dutch patient during her first pregnancy examination. | Giordano PC | Hemoglobin | 2007 | PMID: 17486498 |
Hb Showa-Yakushiji [beta110(G12)Leu-->Pro] in four unrelated patients from west Bengal. | Edison ES | Hemoglobin | 2005 | PMID: 15768552 |
Is it dominantly inherited beta thalassaemia or just a beta-chain variant that is highly unstable? | Thein SL | British journal of haematology | 1999 | PMID: 10520021 |
Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis. | Coleman MB | The Journal of biological chemistry | 1991 | PMID: 2005117 |
Characterization of beta-thalassemia mutations among the Japanese. | Hattori Y | Hemoglobin | 1989 | PMID: 2634667 |
A substitution of cytosine for thymine in codon 110 of the human beta-globin gene is a novel cause of beta-thalassemia phenotypes. | Naritomi Y | Human genetics | 1988 | PMID: 3417300 |
A novel globin structural mutant, Showa-Yakushiji (beta 110 Leu-Pro) causing a beta-thalassemia phenotype. | Kobayashi Y | Blood | 1987 | PMID: 2822177 |
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Text-mined citations for rs35256489 ...
HelpRecord last updated Mar 23, 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.