Submissions for variant NM_014297.5(ETHE1):c.488G>A (p.Arg163Gln)

gnomAD frequency: 0.00002  dbSNP: rs745656120

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000276936	SCV001994850	pathogenic	Ethylmalonic encephalopathy	2021-07-27	reviewed by expert panel	curation	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.
Illumina Laboratory Services, Illumina	RCV000276936	SCV000413488	pathogenic	Ethylmalonic encephalopathy	2017-04-27	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000276936	SCV000894201	pathogenic	Ethylmalonic encephalopathy	2021-10-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000276936	SCV000919304	pathogenic	Ethylmalonic encephalopathy	2018-05-29	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000276936	SCV001583027	pathogenic	Ethylmalonic encephalopathy	2023-12-06	criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000276936	SCV002072929	pathogenic	Ethylmalonic encephalopathy		criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000276936	SCV003821427	pathogenic	Ethylmalonic encephalopathy	2022-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000276936	SCV004192696	pathogenic	Ethylmalonic encephalopathy	2024-03-21	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000276936	SCV005042989	uncertain significance	Ethylmalonic encephalopathy	2024-05-06	criteria provided, single submitter	clinical testing
GeneReviews	RCV000276936	SCV000710832	not provided	Ethylmalonic encephalopathy		no assertion provided	literature only
Natera, Inc.	RCV000276936	SCV001454613	pathogenic	Ethylmalonic encephalopathy	2020-09-16	no assertion criteria provided	clinical testing