ClinVar Genomic variation as it relates to human health
NM_000183.3(HADHB):c.182G>A (p.Arg61His)
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_000183.3(HADHB):c.182G>A (p.Arg61His)
Variation ID: 14845 Accession: VCV000014845.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26263452 (GRCh38) [ NCBI UCSC ] 2: 26486320 (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 21, 2015 Feb 14, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000183.3:c.182G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000174.1:p.Arg61His missense NM_001281512.2:c.182G>A NP_001268441.1:p.Arg61His missense NM_001281513.2:c.116G>A NP_001268442.1:p.Arg39His missense NC_000002.12:g.26263452G>A NC_000002.11:g.26486320G>A NG_007294.1:g.23500G>A P55084:p.Arg61His - Protein change
- R61H, R39H
- Other names
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- Canonical SPDI
- NC_000002.12:26263451: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HADHB | - | - |
GRCh38 GRCh37 |
538 | 565 |
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
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000015970.32 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 24, 2023 | RCV000520375.3 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jun 21, 2021 | RCV003156215.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(May 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616736.3
First in ClinVar: Dec 19, 2017 Last updated: Jul 08, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8651282, 25087612, 28112527, 29915090, 32778825, 31589614, 35383965, 35782614) (less)
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Likely pathogenic
(Mar 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial trifunctional protein deficiency 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002778419.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jun 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial trifunctional protein deficiency 2
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512345.2
First in ClinVar: May 21, 2022 Last updated: Jun 10, 2023 |
Comment:
ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 supporting, PP3 supporting
Geographic origin: Brazil
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Pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial trifunctional protein deficiency 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191813.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial trifunctional protein deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003524178.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 61 of the HADHB protein (p.Arg61His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 61 of the HADHB protein (p.Arg61His). This variant is present in population databases (rs121913132, gnomAD 0.01%). This missense change has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 8651282, 12754706, 16423905). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as R28H and 185G>A (R62H). ClinVar contains an entry for this variant (Variation ID: 14845). 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) performed at Invitae indicates that this missense variant is expected to disrupt HADHB protein function with a positive predictive value of 80%. This variant disrupts the p.Arg61 (also known as p.Arg28) amino acid residue in HADHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12754706). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 1996)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036237.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 01, 2023 |
Comment on evidence:
In a male Caucasian patient who presented with hypoglycemia, hyperammonemia, mild liver dysfunction, and 3-hydroxydicarboxylic aciduria (MTPD2; 620300) at 4 months of age, Ushikubo et … (more)
In a male Caucasian patient who presented with hypoglycemia, hyperammonemia, mild liver dysfunction, and 3-hydroxydicarboxylic aciduria (MTPD2; 620300) at 4 months of age, Ushikubo et al. (1996) described compound heterozygosity for an arg61-to-his (R61H) mutation and an arg247-to-his (R247H; 143450.0003) mutation in the HADHB gene. These were due to nucleotide substitutions 182G-A and 740G-A, respectively. (less)
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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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Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. | Das AM | Clinical chemistry | 2006 | PMID: 16423905 |
Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. | Spiekerkoetter U | Human mutation | 2003 | PMID: 12754706 |
Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. | Ushikubo S | American journal of human genetics | 1996 | PMID: 8651282 |
Text-mined citations for rs121913132 ...
HelpRecord last updated Feb 20, 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.