rs150321966

Variant names:

Your query was ambiguous. Multiple possible variants found:

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 (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

ECHS1
NM_004092.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U:1O:1

Conservation

PhyloP100: 4.80

Variant links:

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]

ECHS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Enoyl-CoA hydratase, mitochondrial (size 262) in uniprot entity ECHM_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) 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 rank	MANE	Protein	UniProt
ECHS1	NM_004092.4 link	c.518C>T	p.Ala173Val	missense_variant	Exon 5 of 8	ENST00000368547.4	NP_004083.3	P30084

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECHS1	ENST00000368547.4 link	c.518C>T	p.Ala173Val	missense_variant	Exon 5 of 8	1	NM_004092.4	ENSP00000357535.3		P30084

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000261

AC:

AN:

245094

Hom.:

AF XY:

0.000308

AC XY:

AN XY:

133022

show subpopulations

Gnomad AFR exome

AF:

0.000252

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000469

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000181

AC:

264

AN:

1457008

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

143

AN XY:

724778

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.0000392

Gnomad4 NFE exome

AF:

0.000208

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000125

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000287

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000363

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

ACMG classification criteria: PM3 very strong, PP1 supporting -

May 05, 2017

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 15, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Jul 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ECHS1: PM3:Strong, PM2, PP1 -

Apr 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 33688149) -

Inborn genetic diseases

Pathogenic:1

Jun 09, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.40

Sift

Benign

0.034

Sift4G

Uncertain

0.037

Polyphen

0.93

Vest4

0.63

MVP

0.59

MPC

1.3

ClinPred

0.52

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over