rs28940289

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP4_ModeratePM3_StrongPP1_StrongPS3_SupportingPM5PP3

This summary comes from the ClinGen Evidence Repository: The ETHE1 c.487C>T mutation is a missense mutation at the 163 amino acid position where one other pathogenic mutation has been reported (c.488G>A) indicating that this residue is critical to the function of the protein (PM5_moderate). There are multiple lines of computational evidence supporting a deleterious effect (PP3_supporting). Functional studies performed in ETHE1 isolated from E-coli cells demonstrated 10 fold reduced ETHE1 catalytic activity when compared to controls (PS3_supporting; PMID:25198162). The c.487C>T mutation has been reported in four unrelated affected individuals including three who were homozygous for the mutation (PMID:16183799; PMID:16828325; PMID:28698729) and one proband where the c. 487C>T was found in trans with another reportedly pathogenic ETHE1 mutation (PMID:18593870) (PM3_strong). One of these patients demonstrated a clinical phenotype specific to ethylmalonic encephalopathy including chronic diarrhea, petechiae, acrocyanosis, and developmental delay in addition to the biochemical findings urinary ethylmalonic acid and elevated blood C4-acylcarnitine esters and blood C5-acylcarnitines (PP4_moderate; PMID:16828325). A larger family including 7 children has been reported where homozygous c.487C>T mutation was identified in the three affected siblings and segregated with disease in the unaffected siblings (PP1_strong; PMID:14732903). In summary, this variant meets criteria to be classified as pathogenic for ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied PM5_moderate; PP3_supporting; PS3_supporting; PM3_strong; PP4_moderate; PP1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115479/MONDO:0011229/014

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ETHE1
NM_014297.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 3.98

Publications

21 publications found

Variant links:

Genes affected

ETHE1 (HGNC:23287): (ETHE1 persulfide dioxygenase) This gene encodes a member of the metallo beta-lactamase family of iron-containing proteins involved in the mitochondrial sulfide oxidation pathway. The encoded protein catalyzes the oxidation of a persulfide substrate to sulfite. Certain mutations in this gene cause ethylmalonic encephalopathy, an infantile metabolic disorder affecting the brain, gastrointestinal tract and peripheral vessels. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ETHE1 Gene-Disease associations (from GenCC):

ethylmalonic encephalopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ETHE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETHE1	NM_014297.5 link	c.487C>T	p.Arg163Trp	missense_variant	Exon 4 of 7	ENST00000292147.7	NP_055112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7 link	c.487C>T	p.Arg163Trp	missense_variant	Exon 4 of 7	1	NM_014297.5	ENSP00000292147.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251460

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111992

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000477

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ethylmalonic encephalopathy

Pathogenic:9Other:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 163 of the ETHE1 protein (p.Arg163Trp). This variant is present in population databases (rs28940289, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of ethylmalonic encephalopathy (PMID: 16828325, 18593870, 30864297). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2317). 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 expected to disrupt ETHE1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETHE1 function (PMID: 25198162). This variant disrupts the p.Arg163 amino acid residue in ETHE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2777167, 14732903, 30298498). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 06, 2021

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The ETHE1 c.487C>T variant is a missense variant at the 163 amino acid position where one other pathogenic mutation has been reported (c.488G>A) indicating that this residue is critical to the function of the protein (PM5_moderate). There are multiple lines of computational evidence supporting a deleterious effect (PP3_supporting). Functional studies performed in ETHE1 isolated from E-coli cells demonstrated 10 fold reduced ETHE1 catalytic activity when compared to controls (PS3_supporting; PMID:25198162). The c.487C>T mutation has been reported in four unrelated affected individuals including three who were homozygous for the variant (PMID:16183799; PMID:16828325; PMID:28698729) and one proband where c.487C>T was found in trans with another reportedly pathogenic ETHE1 variant (PMID:18593870) (PM3_strong). One of these patients demonstrated a clinical phenotype specific to ethylmalonic encephalopathy including chronic diarrhea, petechiae, acrocyanosis, and developmental delay in addition to the biochemical findings urinary ethylmalonic acid and elevated blood C4-acylcarnitine esters and blood C5-acylcarnitines (PP4_moderate; PMID: 16828325). A larger family including 7 children has been reported where homozygous c.487C>T variant was identified in the three affected siblings and segregated with disease in the unaffected siblings (PP1_strong; PMID:14732903). In summary, this variant meets criteria to be classified as pathogenic for ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied PM5_moderate; PP3_supporting; PS3_supporting; PM3_strong; PP4_moderate; PP1_strong. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The ETHE1 c.487C>T (p.Arg163Trp) variant involves the alteration of a conserved nucleotide located at the Metallo-beta-lactamase domain (INterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/278272 control chromosomes at a frequency of 0.0000216, which does not exceed the estimated maximal expected allele frequency of a pathogenic ETHE1 variant (0.0013229). It has been reported in multiple affected individuals in the homozygous state (Tiranti_2004 and Rocco_2006), and a functional study showed the variant with <10% specific activity compared to wild-type (Henriques_2014). Variants affecting the same codon such as R163Q have also been reported affected individuals, supporting the funcitonal importance of this codon. Taken together, this variant is classified as pathogenic. -

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ETHE1: PM3:Strong, PM2, PM5, PP1:Moderate, PP3, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;.

PhyloP100

4.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.7

D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.88

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

4.0

Varity_R

0.95

gMVP

0.95

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over