rs1555761934
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3_SupportingPVS1PM2PP4_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
Consequence
NM_014297.5 frameshift
Scores
Clinical Significance
Conservation
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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
ClinVar
Submissions by phenotype
Ethylmalonic encephalopathy Pathogenic:2Other: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at