ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.389C>T (p.Ala130Val)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.389C>T (p.Ala130Val)
Variation ID: 15245 Accession: VCV000015245.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225653 (GRCh38) [ NCBI UCSC ] 11: 5246883 (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 Mar 17, 2018 Feb 20, 2024 Jun 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.389C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Ala130Val missense NC_000011.10:g.5225653G>A NC_000011.9:g.5246883G>A NG_000007.3:g.71963C>T NG_046672.1:g.3588G>A NG_053049.1:g.1974G>A NG_059281.1:g.6419C>T LRG_1232:g.6419C>T LRG_1232t1:c.389C>T LRG_1232p1:p.Ala130Val P68871:p.Ala130Val - Protein change
- A130V
- Other names
- A129V
- Canonical SPDI
- NC_000011.10:5225652:G: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.
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 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
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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 |
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 | RCV000016450.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001004559.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 14, 2023 | RCV001284158.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 9, 2023 | RCV001804165.10 |
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
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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
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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 27, 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: SCV001469785.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00024 (6/24966 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Individuals who are heterozygous for … (more)
The frequency of this variant in the general population, 0.00024 (6/24966 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Individuals who are heterozygous for this variant have been described as having a normal clinical presentation (PMID: 33489049 (2021)). This variant has also been observed in the compound heterozygous state in patients who had moderate to severe anemia or beta(0)-thalassemia (PMIDs: 32411010 (2020), 27670359 (2017), and 3557994 (1986)). Functional studies indicate that this variant is unstable with decreased oxygen affinity (PMID: 3557994 (1986) and 31553106 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Jun 14, 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: SCV000883979.4
First in ClinVar: Mar 17, 2018 Last updated: Feb 20, 2024 |
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Likely 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: SCV001163641.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(May 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hemoglobinopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697128.5
First in ClinVar: Mar 17, 2018 Last updated: Jun 24, 2023 |
Comment:
Variant summary: HBB c.389C>T (p.Ala130Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: HBB c.389C>T (p.Ala130Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes (gnomAD). The variant, c.389C>T, has been reported in the literature in multiple asymptomatic carriers (Alkindi_2021). To our knowledge, no homozygous occurrence was reported, however, the variant was reported together with a beta-0-thal variant in a clinically asymptomatic individual, who had elevated reticulocyte count (Merault_1986). The variant was also reported in compound heterozygosity with HbC (c.19G>A ,p.Glu7Lys), and HbE (c.79G>A , p.Glu27Lys), in clinically asymptomatic individuals (Merault_1986, Kamseng_2017). In addition, this variant was also reported in compound heterozygosity with HbS (c.20A>T , p.Glu7Val) in several individuals who were affected with mild sickle cell anemia (Merault_1986, Alkindi_2021). These data indicate that the variant maybe associated with a milder disease phenotype, which is dependent on the variant in trans. At least one publication reports experimental evidence indicating that the variant results in a mild decrease in oxygen affinity and precipitation during the isopropanol test, suggestive of an unstable hemoglobin (Merault 1986). The following publications have been ascertained in the context of this evaluation (PMID: 20437613, 33489049, 32411010, 25677748, 26635043, 27670359, 15727901, 17932132, 3557994, 22995479, 26594346, 31553106). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic, one laboratory classified the variant as benign/likely benign, and a third laboratory classified the variant as uncertain significance. In summary, though the variant has not been reported in homozygous form in affected individuals, however, it was reported in several individuals in compound heterozygosity with HbS, who were affected with a milder sickle cell anemia phenotype. Therefore, based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(May 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003439762.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. ClinVar contains an entry for this variant (Variation ID: 15245). This variant is also known as Hb La Desirade. This missense change has been observed in individual(s) with sickle cell anemia (PMID: 33489049). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive beta thalassemia (PMID: 3557994, 27670359); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs111645889, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 130 of the HBB protein (p.Ala130Val). (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 LA DESIRADE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036718.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Merault et al. (1986).
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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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Clinical and Laboratory Features of Hemoglobin La Desirade Variant in Association with Sickle Cell and Alpha Thalassemia Genes. | Alkindi S | Mediterranean journal of hematology and infectious diseases | 2021 | PMID: 33489049 |
Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation. | Flatt JF | Frontiers in physiology | 2020 | PMID: 32411010 |
Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. | Scheps KG | Human mutation | 2020 | PMID: 31553106 |
Low oxygen saturation and severe anemia in compound heterozygous Hb Louisville [β42(CD1)Phe→Leu] and Hb La Desirade [β129(H7)Ala→Val]. | Kamseng P | Hematology (Amsterdam, Netherlands) | 2017 | PMID: 27670359 |
Ten Years of Routine α- and β-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations. | Henderson SJ | Hemoglobin | 2016 | PMID: 26635043 |
Repository of mutations from Oman: The entry point to a national mutation database. | Rajab A | F1000Research | 2015 | PMID: 26594346 |
Broader spectrum of β-thalassemia mutations in Oman: regional distribution and comparison with neighboring countries. | Hassan SM | Hemoglobin | 2015 | PMID: 25677748 |
Pitfalls in the genetic diagnosis of Hb S. | Moradkhani K | Clinical biochemistry | 2013 | PMID: 22995479 |
Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. | Giardine B | Nature genetics | 2011 | PMID: 21423179 |
Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE). | Al-Gazali L | Human mutation | 2010 | PMID: 20437613 |
Mass spectrometry: a tool for enhanced detection of hemoglobin variants. | Kleinert P | Clinical chemistry | 2008 | PMID: 17932132 |
Hb Montfermeil [beta 130(H8) Tyr-->Cys]: suggests a key role for the interaction between helix A and H in oxygen affinity of the hemoglobin molecule. | Kister J | Blood cells, molecules & diseases | 2005 | PMID: 15727901 |
Hemoglobin La Desirade alpha A2 beta 2 129 (H7) Ala----Val: a new unstable hemoglobin. | Merault G | Hemoglobin | 1986 | PMID: 3557994 |
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Text-mined citations for rs111645889 ...
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.