10-133366990-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_004092.4(ECHS1):c.518C>T(p.Ala173Val) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,609,246 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A173A) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00018 ( 1 hom. )
Consequence
ECHS1
NM_004092.4 missense
NM_004092.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 4.80
Genes affected
ECHS1 (HGNC:3151): (enoyl-CoA hydratase, short chain 1) The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004092.4
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-133366990-G-A is Pathogenic according to our data. Variant chr10-133366990-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ECHS1 | NM_004092.4 | c.518C>T | p.Ala173Val | missense_variant | 5/8 | ENST00000368547.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ECHS1 | ENST00000368547.4 | c.518C>T | p.Ala173Val | missense_variant | 5/8 | 1 | NM_004092.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152238Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000261 AC: 64AN: 245094Hom.: 0 AF XY: 0.000308 AC XY: 41AN XY: 133022
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GnomAD4 exome AF: 0.000181 AC: 264AN: 1457008Hom.: 1 Cov.: 33 AF XY: 0.000197 AC XY: 143AN XY: 724778
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152238Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12AN XY: 74376
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency Pathogenic:6Uncertain:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense variant c.518C>T(p.Ala173Val) in ECHS1 gene has been reported previously in compound heterozygous state in multiple individuals with ECHS1-related conditions (Illsinger S, et al., 2020, Olgiati S, et al., 2016). This variant is reported to being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The c.518C>T variant has 0.02% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic/Uncertain Significance. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid Alanine at position 173 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Ala173Val in ECHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 15, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, flagged submission | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Sep 23, 2022 | ACMG classification criteria: PM3 very strong, PP1 supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 05, 2017 | Two heterozygous variants were identified in the ECHS1 gene, NM_004092.3(ECHS1):c.518C>T and NM_004092.3(ECHS1):c.541C>T. The NM_004092.3(ECHS1):c.518C>T missense variant is in exon 5 of the ECHS1 gene (chr10:135180494). This substitution is predicted to create a change of an alanine to a valine at amino acid position 173, NP_004083.3(ECHS1):p.(Ala173Val), which is NOT considered significant. The alanine at this position has low conservation and therefore Grantham assessment (A-GVGD) is unlikely pathogenic. In silico software predictions of the pathogenicity of this variant are conflicting. It is situated within a known functional region (conserved trimeric quaternary structure which contains the catalytic core). This variant has not been previously observed in our patient cohort but it has been observed in a population database at a frequency of 0.04% (ExAC). It has been previously reported in a compound heterozygous state in three individuals presenting with later-onset movement disorders (Olgiati et al 2016, Mahajan et al 2017). Additional biochemical evaluation in this patient was consistent with ECHS1 deficiency. Based on current information and biochemical evidence, this variant has been classified as LIKELY PATHOGENIC. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 16, 2017 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the ECHS1 protein (p.Ala173Val). This variant is present in population databases (rs150321966, gnomAD 0.04%). This missense change has been observed in individual(s) with ECHS1-related conditions (PMID: 27090768, 28039521, 30008475, 32677093, 32858208). 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. ClinVar contains an entry for this variant (Variation ID: 377257). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | ECHS1: PM3:Strong, PM2, PP1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2023 | 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: 31219693, 33931985, 32777769, 30008475, 28039521, 27090768, 29882869, 26099313, 31628766, 32858208, 33929620, 34140924, 34716721, 32677093, 33258288, 35856138, 35206276, 34052969, Das_2022_Abstract, 36200804, 35394834, 36883047) - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at