ClinVar Genomic variation as it relates to human health
NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg)
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.476A>G (p.Gln159Arg)
Variation ID: 379794 Accession: VCV000379794.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.3 10: 133368961 (GRCh38) [ NCBI UCSC ] 10: 135182465 (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 Aug 4, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004092.4:c.476A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004083.3:p.Gln159Arg missense NC_000010.11:g.133368961T>C NC_000010.10:g.135182465T>C NG_042077.1:g.9444A>G - Protein change
- Q159R
- Other names
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- Canonical SPDI
- NC_000010.11:133368960: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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Allele frequency
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The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00012
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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ECHS1 | - | - |
GRCh38 GRCh37 |
298 | 465 |
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
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
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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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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Sep 30, 2020 | RCV000578268.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000432904.21 | |
See cases
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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2021 | RCV002252122.3 |
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: SCV001244721.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
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Pathogenic
(Jan 28, 2018)
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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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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244960.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A heterozygous missense variant, NM_004092.3(ECHS1):c.476A>G, has been identified in exon 4 of 8 of the ECHS1 gene. The variant is predicted to result in a … (more)
A heterozygous missense variant, NM_004092.3(ECHS1):c.476A>G, has been identified in exon 4 of 8 of the ECHS1 gene. The variant is predicted to result in a moderate amino acid change from glutamine to arginine at position 159 of the protein (NP_004083.3(ECHS1):p.(Gln159Arg)). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. The variant is present in the gnomAD database at a frequency of 0.01% (29 heterozygotes, 0 homozygotes). The variant has previously been reported as likely pathogenic in ClinVar and is reported multiple times in the liteature in patients with deficiency of shortchain enoyl-CoA hydratase (Ganetzky RD et al., 2016, Haack TB et al.; 2015, Tetreault M et al., 2015, Ferdinandusse S et al.; 2015). One of these reports showed significantly reduced enzymatic activity in a patient that was compound heterozygous for this variant (Ferdinandusse S et al.; 2015). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 2
Clinical Features:
Increased serum lactate (present) , Morphological abnormality of the central nervous system (present)
Family history: yes
Secondary finding: no
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Likely pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: research
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Cologne University
Accession: SCV001441222.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002522883.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS4, PM2, PM3, PP1, PP4, BP4
Clinical Features:
Telecanthus (present) , Seizure (present) , Obesity (present) , Neurodevelopmental abnormality (present) , Macrocephaly (present) , Depressed nasal bridge (present) , Telecanthus (present) , Seizure … (more)
Telecanthus (present) , Seizure (present) , Obesity (present) , Neurodevelopmental abnormality (present) , Macrocephaly (present) , Depressed nasal bridge (present) , Telecanthus (present) , Seizure (present) , Obesity (present) , Neurodevelopmental abnormality (present) , Macrocephaly (present) , Depressed nasal bridge (present) (less)
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Pathogenic
(Nov 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline,
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680203.2
First in ClinVar: Feb 08, 2018 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Optic atrophy (present) , Brain atrophy (present) , Focal seizures, afebril (present) , Iron deficiency anemia (present) , Epileptic encephalopathy (present) , Hearing impairment (present) … (more)
Optic atrophy (present) , Brain atrophy (present) , Focal seizures, afebril (present) , Iron deficiency anemia (present) , Epileptic encephalopathy (present) , Hearing impairment (present) , Hypoplasia of the corpus callosum (present) , Global developmental delay (present) (less)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
3-Methylglutaconic aciduria (present) , Microcephaly (present) , Hearing impairment (present)
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Likely pathogenic
(-)
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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:
biparental
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004042689.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 28, 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: SCV000517223.7
First in ClinVar: Mar 08, 2017 Last updated: Nov 25, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28409271, 32800686, 26081110, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28409271, 32800686, 26081110, 26099313, 26000322, 29575569, 29882869, 29923089, 32573669, 32329585, 32313153, 34426522, 33574353, 32677093, 35568357, 35098523) (less)
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Likely pathogenic
(Feb 06, 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: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024457.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 02, 2024)
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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: SCV002190789.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 159 of the ECHS1 protein (p.Gln159Arg). … (more)
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 159 of the ECHS1 protein (p.Gln159Arg). This variant is present in population databases (rs375032130, gnomAD 0.03%). This missense change has been observed in individual(s) with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (PMID: 26081110, 26099313, 28409271, 29575569). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 379794). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821557.12
First in ClinVar: Jan 21, 2023 Last updated: Aug 04, 2024 |
Comment:
ECHS1: PM3:Very Strong, PM2
Number of individuals with the variant: 3
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Pathogenic
(Jul 13, 2020)
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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: SCV001422319.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment on evidence:
In 3 sibs (proband 68552) with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), who were born to consanguineous Pakistani parents (family 3), Haack et al. … (more)
In 3 sibs (proband 68552) with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D; 616277), who were born to consanguineous Pakistani parents (family 3), Haack et al. (2015) identified a homozygous c.476A-G transition (c.476A-G, NM_004092.3) in exon 4 of the ECHS1 gene, resulting in a gln159-to-arg (Q159R) substitution. The mutation was identified by whole-exome sequencing in 1 sib and confirmed by Sanger sequencing from blood spots in the 2 other sibs (identical female twins), who were deceased. The parents were heterozygous for the mutation. Haack et al. (2015) identified the Q159R mutation in compound heterozygosity with different ECHS1 mutations in 2 unrelated patients with ECHS1D: patient 346 (family 1) had the previously identified N9S mutation (602292.0005) and patient 52236 (family 10) had a c.229G-C transversion, resulting in a glu77-to-gln (E77Q; 602292.0009) substitution. Immunoblot analysis on fibroblasts from patients 346 and 52236 showed reduced expression of the ECHS1 protein; reduced palmitate-dependent respiration and reduced 2-enoyl-CoA hydratase activity was found in the fibroblasts of patient 52236. The Q159R variant had an allele frequency of 0.0001148 in the ExAC database, and the E77Q was not present in the database. In 3 Irish Traveler sibs with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the Q159R mutation in the ECHS1 gene. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids of all patients. Muscle and fibroblast testing was carried out in 1 sib. 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. For discussion of the Q159R mutation in the ESCHS1 gene that was found in compound heterozygosity in a patient (P4) with ESCHS1D by Tetreault et al. (2015), see 602292.0009. (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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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 |
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 |
Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency. | Balasubramaniam S | Journal of inherited metabolic disease | 2017 | PMID: 28409271 |
Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. | Tetreault M | Human genetics | 2015 | PMID: 26099313 |
Clinical and biochemical characterization of four patients with mutations in ECHS1. | Ferdinandusse S | Orphanet journal of rare diseases | 2015 | PMID: 26081110 |
Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. | Haack TB | Annals of clinical and translational neurology | 2015 | PMID: 26000322 |
Text-mined citations for rs375032130 ...
HelpRecord last updated Aug 04, 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.