ClinVar Genomic variation as it relates to human health
NM_000183.3(HADHB):c.181C>T (p.Arg61Cys)
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(2); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000183.3(HADHB):c.181C>T (p.Arg61Cys)
Variation ID: 449456 Accession: VCV000449456.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26263451 (GRCh38) [ NCBI UCSC ] 2: 26486319 (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 Dec 19, 2017 Feb 14, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000183.3:c.181C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000174.1:p.Arg61Cys missense NM_001281512.2:c.181C>T NP_001268441.1:p.Arg61Cys missense NM_001281513.2:c.115C>T NP_001268442.1:p.Arg39Cys missense NC_000002.12:g.26263451C>T NC_000002.11:g.26486319C>T NG_007294.1:g.23499C>T - Protein change
- R61C, R39C
- Other names
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- Canonical SPDI
- NC_000002.12:26263450:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
541 | 569 |
Conditions - Germline
Condition
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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 26, 2020 | RCV000518877.2 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 1, 2023 | RCV001197680.6 |
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
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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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Uncertain significance
(Mar 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial trifunctional protein deficiency 1
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368459.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
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Likely pathogenic
(Jun 26, 2020)
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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: SCV000617634.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28112527, 12754706) (less)
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Pathogenic
(Oct 10, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122668.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: HADHB c.181C>T (p.Arg61Cys aka. R28C) results in a non-conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) of the encoded protein … (more)
Variant summary: HADHB c.181C>T (p.Arg61Cys aka. R28C) results in a non-conservative amino acid change located in the Thiolase, N-terminal domain (IPR020616) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251490 control chromosomes (gnomAD). The variant c.181C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Mitochondrial Trifunctional Protein Deficiency (e.g. Spiekerkoetter_2003, Spiekerkoetter_2004, Schwantje_2022). These data indicate that the variant is likely to be associated with disease. Publication also reported reports experimental evidence evaluating an impact on protein function and demonstrated decreased enzyme activities in patient derived cells (Spiekerkoetter_2003, Spiekerkoetter_2004, Schwantje_2022), and decreased expression and abolished protein interaction with HADHA in an in vitro expression system (Naiki_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24664533, 12754706, 14694500, 35383965). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, while the other submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Oct 26, 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: SCV004191806.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 01, 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: SCV004292064.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 61 of the HADHB protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 61 of the HADHB protein (p.Arg61Cys). This variant is present in population databases (rs780351691, gnomAD 0.006%). This missense change has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 12754706). This variant is also known as R28C. ClinVar contains an entry for this variant (Variation ID: 449456). 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 amino acid residue in HADHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8651282, 12754706, 16423905). 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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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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Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands. | Schwantje M | Journal of inherited metabolic disease | 2022 | PMID: 35383965 |
Mutations in HADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. | Naiki M | American journal of medical genetics. Part A | 2014 | PMID: 24664533 |
Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. | Das AM | Clinical chemistry | 2006 | PMID: 16423905 |
Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein. | Spiekerkoetter U | Muscle & nerve | 2004 | PMID: 14694500 |
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 rs780351691 ...
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.