rs587776498

chr10-133373329-G-Achr10-133373329-G-Cchr10-133373329-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_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

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_004092.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-133373329-G-A is Pathogenic according to our data. Variant chr10-133373329-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 156434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-133373329-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECHS1	NM_004092.4 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/8	ENST00000368547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECHS1	ENST00000368547.4 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/8	1	NM_004092.4	P1

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

GnomAD3 exomes

AF:

0.0000101

AC:

AN:

98522

Hom.:

AF XY:

0.0000182

AC XY:

AN XY:

54884

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000664

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000290

Gnomad4 NFE exome

AF:

0.0000338

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2019	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) -

Leigh syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

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

- -

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

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

MutationTaster

Benign

1.0

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.20

gMVP

0.82

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

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