rs1555761934

Positions:

• chr19-43508051-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3_Supporting PVS1 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.604dupG; p.V202FsX220 variant in the ETHE1 gene is a frameshift variant resulting in truncation greater than 50 bp upstream of the final exon and is predicted to undergo nonsense mediated decay (PVS1). This variant is absent from population databases (PM2). A single homozygote is reported in multiple publications (PMID:14732903, PMID:16183799, PMID:18593870), confirmed through linkage analysis (PM3_supporting; scored 0.5 per SVI PM3 guidance v1.). PMID:14732903 reports this patient initially with a classic presentation of ethylmalonic encephalopathy, including acrocyanosis, petechiae, chronic diarrhea and developmental delay with urinary ethylmalonic aciduria of 320 mg/g creatine (PP4_moderate). In summary, this variant meets criteria to be classified as a pathogenic of ETHE1-related ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied: (PVS1, PM2, PM3_supporting, PP4_moderate,). This was reviewed with the ETHE1 expert panel on 2/23/2021 and approved on 2/23/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658799240/MONDO:0011229/014

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETHE1 NM_014297.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 2.92

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 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETHE1	NM_014297.5	c.604_605insG	p.Val202GlyfsTer19	frameshift_variant	6/7	ENST00000292147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETHE1	ENST00000292147.7	c.604_605insG	p.Val202GlyfsTer19	frameshift_variant	6/7	1	NM_014297.5	P1
ETHE1	ENST00000600651.5	c.604_605insG	p.Val202GlyfsTer19	frameshift_variant	6/6	1
ETHE1	ENST00000594342.5	c.*167_*168insG		3_prime_UTR_variant, NMD_transcript_variant	5/6	2
ETHE1	ENST00000598330.1	c.*167_*168insG		3_prime_UTR_variant, NMD_transcript_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	May 07, 2021	The c.604dupG; p.V202FsX220 variant in the ETHE1 gene is a frameshift variant resulting in truncation greater than 50 bp upstream of the final exon and is predicted to undergo nonsense mediated decay (PVS1). This variant is absent from population databases (PM2). A single homozygote is reported in multiple publications (PMID: 14732903, PMID: 16183799, PMID: 18593870), confirmed through linkage analysis (PM3_supporting; scored 0.5 per SVI PM3 guidance v1.). PMID: 14732903 reports this patient initially with a classic presentation of ethylmalonic encephalopathy, including acrocyanosis, petechiae, chronic diarrhea and developmental delay with urinary ethylmalonic aciduria of 320 mg/g creatine (PP4_moderate). In summary, this variant meets criteria to be classified as a pathogenic of ETHE1-related ethylmalonic encephalopathy in an autosomal recessive manner. ETHE1-specific ACMG/AMP criteria applied: (PVS1, PM2, PM3_supporting, PP4_moderate). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1555761934; hg19: chr19-44012203;