rs28940289

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3PM3_StrongPP1_StrongPS3_SupportingPP4_Moderate

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
ENST00000292147.7 missense

Scores

15

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 3.98

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
ETHE1	NM_014297.5 linkuse as main transcript	c.487C>T	p.Arg163Trp	missense_variant	4/7	ENST00000292147.7	NP_055112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7 linkuse as main transcript	c.487C>T	p.Arg163Trp	missense_variant	4/7	1	NM_014297.5	ENSP00000292147	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152146

Hom.:

0

Cov.:

32

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

GnomAD3 exomes

AF:

0.0000239

AC:

6

AN:

251460

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135910

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 SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

20

AN:

1461866

Hom.:

0

Cov.:

31

AF XY:

0.0000165

AC XY:

12

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152146

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.0000247

AC:

3

Asia WGS

AF:

0.000289

AC:

1

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	May 06, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

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

D

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

34

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.90

D

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.20

D

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.7

H;.

MutationTaster

Benign

1.0

A

PrimateAI

Pathogenic

0.87

D

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

D

GERP RS

4.0

Varity_R

0.95

gMVP

0.95

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

LitVar

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

Other links and lift over

dbSNP: rs28940289; hg19: chr19-44015607;