ClinVar Genomic variation as it relates to human health
NM_004092.4(ECHS1):c.538A>G (p.Thr180Ala)
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_004092.4(ECHS1):c.538A>G (p.Thr180Ala)
Variation ID: 691284 Accession: VCV000691284.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.3 10: 133366970 (GRCh38) [ NCBI UCSC ] 10: 135180474 (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 Sep 28, 2019 Feb 14, 2024 Jun 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004092.4:c.538A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004083.3:p.Thr180Ala missense NC_000010.11:g.133366970T>C NC_000010.10:g.135180474T>C NG_042077.1:g.11435A>G - Protein change
- T180A
- Other names
- -
- Canonical SPDI
- NC_000010.11:133366969:T:C
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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 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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. |
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ECHS1 | - | - |
GRCh38 GRCh37 |
293 | 460 |
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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2020 | RCV000851532.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 20, 2023 | RCV001564785.8 |
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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Kids Research, The Children's Hospital at Westmead
Accession: SCV001244722.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
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Pathogenic
(Apr 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Affected status: yes
Allele origin:
maternal
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Elsea Laboratory, Baylor College of Medicine
Accession: SCV001424289.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Sex: male
Testing laboratory: Org: 1006
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Pathogenic
(Mar 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520540.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Oct 13, 2022)
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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: SCV001788000.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29923089, 31219693, 26920905, 29575569, 32800686, 26099313, 30848071, 29882869, 32313153, 28202214, 28409271, 26839416, 33586140, 32013919, 31944285) (less)
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Likely pathogenic
(Dec 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024452.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 20, 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: SCV002229788.3
First in ClinVar: Mar 28, 2022 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) performed at Invitae indicates that this missense variant is not expected to disrupt ECHS1 protein function. ClinVar contains an entry for this variant (Variation ID: 691284). This missense change has been observed in individual(s) with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (PMID: 26099313). 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 is present in population databases (rs557128093, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 180 of the ECHS1 protein (p.Thr180Ala). (less)
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Pathogenic
(Aug 12, 2021)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL SHORT-CHAIN ENOYL-CoA HYDRATASE 1 DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001422322.2
First in ClinVar: Jul 16, 2020 Last updated: Aug 21, 2021 |
Comment on evidence:
In 4 patients from 3 unrelated French Canadian families with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Tetreault et al. (2015) identified compound heterozygous mutations … (more)
In 4 patients from 3 unrelated French Canadian families with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), Tetreault et al. (2015) identified compound heterozygous mutations in the ECHS1 gene. All patients had a c.538A-G transition (c.538A-G, NM_004092) in exon 5, resulting in a thr180-to-ala (T180A) substitution; in patient 1 (P1), the second mutation was a c.583G-A transition in exon 5, resulting in a gly195-to-ser (G195S; 602292.0010) substitution; in 2 sibs (P2 and P3), the second mutation was a c.713C-T transition in exon 6, resulting in an ala238-to-val (A238V; 602292.0011) substitution; and in P4, the second mutation was Q159R (602292.0007). The mutations segregated with the disorder in the families. All of the mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. None of these variants were present in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases, except for Q159R, which was reported once in EVS. All 4 mutations were in the ECHS1 enoyl-CoA hydratase/isomerase domain and were predicted to decrease protein stability. Tetreault et al. (2015) found that the patients with the T180A variant shared a common haplotype, suggesting that the variant derives from a single ancestral mutation. The haplotype was not observed in 10 unrelated French Canadian control samples. In a Pakistani patient with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the T180A mutation. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids. Patient fibroblasts showed markedly decreased ECHS1 enzyme activity and absence of ECHS1 on Western blot analysis. PDH activity and beta oxidation studies were normal. Activities of respiratory chain complexes I, II, and IV were normal, and activity of complexes II+III was decreased in muscle. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000994605.2
First in ClinVar: Sep 28, 2019 Last updated: Oct 01, 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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The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease. | Riley LG | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32313153 |
Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency. | Adam MP | - | 2019 | PMID: 31219693 |
Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. | Fitzsimons PE | American journal of medical genetics. Part A | 2018 | PMID: 29575569 |
Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. | Tetreault M | Human genetics | 2015 | PMID: 26099313 |
Text-mined citations for rs557128093 ...
HelpRecord last updated Mar 17, 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.