rs28940289

Positions:

• chr19-43511455-G-A
• chr19-43511455-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP3 PP1_Strong PM3_Strong PM5 PP4_Moderate PS3_Supporting

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
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 3.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETHE1	NM_014297.5	c.487C>T	p.Arg163Trp	missense_variant	4/7	ENST00000292147.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32

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

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

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

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:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Pathogenic:9 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	Baylor Genetics	Mar 19, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Fulgent Genetics, Fulgent Genetics	Apr 23, 2022	- -

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

Other links and lift over

dbSNP: rs28940289; hg19: chr19-44015607;