19-43511454-C-T

Position:

• chr19-43511454-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_Supporting PP4_Moderate PM5 PP3 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.488G>A (NM_014297.5) variant in ETHE1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 163 (p.R163Q). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 (13/251,458 alleles) in the general population, which is higher than the ClinGen ETHE1 threshold < 0.00002 for PM2, thus it does not meet this criterion. This variant was originally reported in two compound heterozygous (c.131_132delAG; p. E44fsX105) relatives who both had developmental delay, petechiae, orthostatic acrocyanosis, chronic diarrhea, and ethylmalonic aciduria which is a phenotype highly specific to ethylmalonic encephalopathy (PP4_moderate; PMID:14732903). This variant has been detected in at least 9 patients reported in the literature with ethylmalonic encephalopathy, however, many of the cases are not scoreable according to the SVI recommendation for in trans criterion for PM3, as parental phasing was not performed or the second variant was a VUS (PMID:18593870; PMID:16183799, PMID:30298498). After review of scoreable cases, it was determined by the ETHE1 VCEP that four reported cases were scorable. A single relative from family L from PMID:14732903 was awarded 1.0 as this patient was a compound heterozygote for an upstream truncating variant (c.131_132delAG; p. E44fsX105), which was confirmed in trans by segregation analysis. Additionally, while the p.E44fsX105 has not been formally curated at this time, given that the p.E44fsX105 is a truncating variant that is predicted to undergo nonsense mediated decay, it is also a strong candidate for a pathogenic classification; the VCEP agreed that this was justification to score this case as 1.0. Patients reported in PMID:22020834 and PMID:27771676 were each awarded 0.25 for their respective VUS’s, which were also confirmed in trans. A homozygous patient reported in PMID:27391121 in whom homozygosity was confirmed via trio WES including parental samples was scored 0.5. This was confirmed by Baylor Genetics who performed the testing for this study (PM3_Strong; Total score- 2.0). ETHE1 encodes persulfide dioxygenase. Persulfide dioxygenase activity measured in recombinant human ETHE1 proteins (both wild-type and p.R163Q) expressed in E.Coli (purified to homogeneity) showed that the p.R163Q recombinant E.Coli only exhibited ~10% of wild-type catalytic activity, indicating that this variant impacts protein function (PS3_supporting; PMID:25198162). One other missense variant [c.487C>T, p.R163W; PMID 14732903, PMID 16828325, PMID 16183799, PMID 28698729; ClinVar Variation ID: 2317], in the same codon has been classified as pathogenic for ethylmalonic encephalopathy by the ClinGen ETHE1 VCEP (PM5). The computational predictor [REVEL] gives a score of 0.928, which is above the threshold of 0.75, evidence that correlates with impact on ETHE1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): PM3_strong, PP4_Moderate, PS3_supporting, PM5, PP3. Approved 7/12/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA320215/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ETHE1 NM_014297.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:1 O:1
• Conservation: PhyloP100: 6.47

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 10 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.
• 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	c.488G>A	p.Arg163Gln	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	c.488G>A	p.Arg163Gln	missense_variant	4/7	1	NM_014297.5	ENSP00000292147.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251458 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Pathogenic:10 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PS3,PM3(strong),PM5,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ETHE1 c.488G>A (p.Arg163Gln) variant has been reported in at least three studies in which it was found in a homozygous state in two individuals and in a compound heterozygous state in four individuals, all with ethylmalonic encephalopathy (Tiranti et al. 2006; Mineri et al. 2008; Papetti et al. 2015). In one of the compound heterozygotes, the p.Arg163Gln variant was found to be in trans with a stop-gained variant and in cis with an additional missense variant located in a non-conserved residue (Papetti et al. 2015). The p.Arg163Gln variant was absent from 200 control individuals (Tiranti et al. 2004) and is reported at a frequency of 0.00035 in the Latino population of the Exome Aggregation Consortium. The variant is located in a well-conserved residue in the catalytic domain of the protein. Functional expression studies in E. coli showed that the p.Arg163Gln variant significantly reduced the conformational stability and activity of the ETHE1 protein compared to wildtype (Henriques et al. 2014). Based on the collective evidence, the p.Arg163Gln variant is classified as pathogenic for ethylmalonic encephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 163 of the ETHE1 protein (p.Arg163Gln). This variant is present in population databases (rs745656120, gnomAD 0.03%). This missense change has been observed in individuals with ethylmalonic encephalopathy (PMID: 14732903, 18593870, 26194623, 27771676, 30298498). ClinVar contains an entry for this variant (Variation ID: 214322). 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 observed in individuals with ETHE1-related conditions (PMID: 16828325, 17712735, 30298498), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Jul 27, 2021	The c.488G>A (NM_014297.5) variant in ETHE1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 163 (p.R163Q). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 (13/251,458 alleles) in the general population, which is higher than the ClinGen ETHE1 threshold < 0.00002 for PM2, thus it does not meet this criterion. This variant was originally reported in two compound heterozygous (c.131_132delAG; p. E44fsX105) relatives who both had developmental delay, petechiae, orthostatic acrocyanosis, chronic diarrhea, and ethylmalonic aciduria which is a phenotype highly specific to ethylmalonic encephalopathy (PP4_moderate; PMID: 14732903). This variant has been detected in at least 9 patients reported in the literature with ethylmalonic encephalopathy, however, many of the cases are not scoreable according to the SVI recommendation for in trans criterion for PM3, as parental phasing was not performed or the second variant was a VUS (PMID: 18593870; PMID: 16183799, PMID: 30298498). After review of scoreable cases, it was determined by the ETHE1 VCEP that four reported cases were scorable. A single relative from family L from PMID: 14732903 was awarded 1.0 as this patient was a compound heterozygote for an upstream truncating variant (c.131_132delAG; p. E44fsX105), which was confirmed in trans by segregation analysis. Additionally, while the p.E44fsX105 has not been formally curated at this time, given that the p.E44fsX105 is a truncating variant that is predicted to undergo nonsense mediated decay, it is also a strong candidate for a pathogenic classification; the VCEP agreed that this was justification to score this case as 1.0. Patients reported in PMID: 22020834 and PMID: 27771676 were each awarded 0.25 for their respective VUS’s, which were also confirmed in trans. A homozygous patient reported in PMID: 27391121 in whom homozygosity was confirmed via trio WES including parental samples was scored 0.5. This was confirmed by Baylor Genetics who performed the testing for this study (PM3_Strong; Total score- 2.0). ETHE1 encodes persulfide dioxygenase. Persulfide dioxygenase activity measured in recombinant human ETHE1 proteins (both wild-type and p.R163Q) expressed in E.Coli (purified to homogeneity) showed that the p.R163Q recombinant E.Coli only exhibited ~10% of wild-type catalytic activity, indicating that this variant impacts protein function (PS3_supporting; PMID: 25198162). One other missense variant [c.487C>T, p.R163W; PMID 14732903, PMID 16828325, PMID 16183799, PMID 28698729; ClinVar Variation ID: 2317], in the same codon has been classified as pathogenic for ethylmalonic encephalopathy by the ClinGen ETHE1 VCEP (PM5). The computational predictor [REVEL] gives a score of 0.928, which is above the threshold of 0.75, evidence that correlates with impact on ETHE1 function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): PM3_strong, PP4_Moderate, PS3_supporting, PM5, PP3. Approved 7/12/2021. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R163Q in ETHE1 (NM_014297.5) has been previously reported in homozygous as well as compound heterozygous state in affected individuals (Papetti L et al; Al-Shamsi A et al).Functional studies suggest a detrimental effect (Henriques BJ et al). The variant has been submitted to ClinVar as Pathogenic. The p.R163Q variant is observed in 13 alleles in the gnomAD exomes (MAF=0.005%) and is novel (not in any individuals) in 1000 Genomes. The p.R163Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 163 of ETHE1 is conserved in all mammalian species. The nucleotide c.488 in ETHE1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2018	Variant summary: ETHE1 c.488G>A (p.Arg163Gln) results in a conservative amino acid change located in the Metallo-beta-lactamase (IPR001279) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246246 control chromosomes (gnomAD). The variant, c.488G>A, has been reported commonly in the literature in multiple individuals affected with Ethylmalonic Encephalopathy (Mineri_2008, Al-Shamsi_2016). Urine organic acid and acylglycine profiles were consistent with ethylmalonic encepathopathy. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Henriques_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.98		Loss of methylation at R163 (P = 0.0695);Loss of methylation at R163 (P = 0.0695);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.93

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

Other links and lift over

dbSNP: rs745656120; hg19: chr19-44015606; COSMIC: COSV52678756; COSMIC: COSV52678756;