rs1555761934

Variant names:

• chr19-43508051-A-AC
• rs1555761934
• NM_014297.5:c.604dupG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP4_Moderate PM3_Supporting

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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ethylmalonic encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Specifications for ETHE1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014297.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	NM_014297.5	MANE Select	c.604dupG	p.Val202GlyfsTer19	frameshift	Exon 6 of 7	NP_055112.2
	ETHE1	NM_001320867.2		c.571dupG	p.Val191GlyfsTer19	frameshift	Exon 6 of 7	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.310dupG	p.Val104GlyfsTer19	frameshift	Exon 4 of 5	NP_001307798.1	A0A0S2Z5N8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.604dupG	p.Val202GlyfsTer19	frameshift	Exon 6 of 7	ENSP00000292147.1	O95571
	ETHE1	ENST00000600651.5	TSL:1	c.604dupG	p.Val202GlyfsTer19	frameshift	Exon 6 of 6	ENSP00000469037.1	M0QXB5
	ETHE1	ENST00000880125.1		c.769dupG	p.Val257GlyfsTer19	frameshift	Exon 7 of 8	ENSP00000550184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Ethylmalonic encephalopathy (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555761934; hg19: chr19-44012203;