rs587776498

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong

The NM_004092.4(ECHS1):c.5C>T(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000306 in 1,502,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

ECHS1
NM_004092.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.12

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ECHS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004092.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8627 (below the threshold of 3.09). Trascript score misZ: 0.70218 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.

PP5

Variant 10-133373329-G-A is Pathogenic according to our data. Variant chr10-133373329-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156434.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.5C>T	p.Ala2Val	missense_variant	Exon 1 of 8	ENST00000368547.4	NP_004083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECHS1	ENST00000368547.4 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 8	1	NM_004092.4	ENSP00000357535.3

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000101

AC:

AN:

98522

AF XY:

0.0000182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000288

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000296

AC:

AN:

1350540

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

666302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27752

American (AMR)

AF:

0.00

AC:

AN:

32798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23742

East Asian (EAS)

AF:

0.0000664

AC:

AN:

30140

South Asian (SAS)

AF:

0.00

AC:

AN:

76730

European-Finnish (FIN)

AF:

0.0000290

AC:

AN:

34522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4508

European-Non Finnish (NFE)

AF:

0.0000338

AC:

AN:

1064012

Other (OTH)

AF:

0.0000178

AC:

AN:

56336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Pathogenic:4

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ECHS1 c.5C>T; p.Ala2Val variant (rs587776498) is reported in the literature in the compound heterozygous state in several individuals affected with Leigh syndrome (Kuwajima 2021, Ogawa 2020, Sakai 2015, Sato-Shirai 2021, Stenton 2022, Sun 2020, Uesugi 2020, Yang 2022). This variant is also reported in ClinVar (Variation ID: 156434), but is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 2 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.604). However, functional analyses of the variant protein show decreased expression and enzyme activity (Sakai 2015). Based on available information, this variant is considered to be pathogenic. References: Kuwajima M et al. Valine metabolites analysis in ECHS1 deficiency. Mol Genet Metab Rep. 2021 Oct 9;29:100809. PMID: 34667719. Ogawa E et al. Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis. J Inherit Metab Dis. 2020 Jul;43(4):819-826. PMID: 31967322. Sakai C et al. ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. 2015 Feb;36(2):232-9. PMID: 25393721. Sato-Shirai I et al. Valine-restricted diet for patients with ECHS1 deficiency: Divergent clinical outcomes in two Japanese siblings. Brain Dev. 2021 Feb;43(2):308-313. PMID: 33139125. Stenton SL et al. Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital. Ann Neurol. 2022 Apr;91(4):466-482. PMID: 35094435. Sun D et al. Novel ECHS1 mutations in Leigh syndrome identified by whole-exome sequencing in five Chinese families: case report. BMC Med Genet. 2020 Jul 16;21(1):149. PMID: 32677908. Uesugi M et al. Short-chain enoyl-CoA hydratase deficiency causes prominent ketoacidosis with normal plasma lactate levels: A case report. Mol Genet Metab Rep. 2020 Oct 30;25:100672. PMID: 33163364. Yang Z et al. Whole-exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees. Am J Med Genet A. 2022 Apr;188(4):1214-1225. PMID: 35014173. -

Feb 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Nov 04, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect as A2V was associated with a reduction in protein expression and enzyme activity (Sakai et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25393721, 31967322, 33139125, 32677908, 33163364) -

Mar 10, 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 2 of the ECHS1 protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ECHS1-related conditions (PMID: 25393721, 32677908, 33139125, 33163364). 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: 156434). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change alters ECHS1 gene expression (PMID: 25393721). For these reasons, this variant has been classified as Pathogenic. -

Leigh syndrome

Pathogenic:1

Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.041

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

PhyloP100

4.1

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.60

Sift

Uncertain

0.0050

Sift4G

Benign

0.12

Polyphen

0.011

Vest4

0.80

MutPred

0.39

Gain of stability (P = 0.0061);

MVP

0.90

MPC

0.46

ClinPred

0.50

GERP RS

2.8

PromoterAI

-0.60

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.20

gMVP

0.82

Mutation Taster

=90/10

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over