Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_014297.5(ETHE1):c.604dup (p.Val202fs)

CA658799240

504504 (ClinVar)

Gene: ETHE1

Condition: ethylmalonic encephalopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: afe48119-3f05-410f-8987-7559d29b982c

Approved on: 2021-05-07

Published on: 2021-05-07

HGVS expressions

NM_014297.5:c.604dup

NM_014297.5(ETHE1):c.604dup (p.Val202fs)

ENST00000292147.7:c.604dup

ENST00000292147.6:c.604dup

ENST00000594342.5:c.*167dup

ENST00000598330.1:c.*167dup

ENST00000600651.5:c.604dup

NM_014297.3:c.604dup

NM_001320867.1:c.571dup

NM_001320868.1:c.235dup

NM_001320869.1:c.310dup

NM_014297.4:c.604dup

NM_001320867.2:c.571dup

NM_001320868.2:c.235dup

NM_001320869.2:c.310dup

NC_000019.10:g.43508052dup

CM000681.2:g.43508052dup

NC_000019.9:g.44012204dup

CM000681.1:g.44012204dup

NC_000019.8:g.48704044dup

NG_008141.1:g.24193dup

Pathogenic

PVS1 PM2 PP4_Moderate PM3_Supporting

PS3 PP1 BA1 BS1 BS2

Evidence Links 0

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

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.

PVS1

c.604dupG;p.V202FsX220 results in truncation of ETHE1 greater than 50 bp upstream in ensembl of exon7; predicted to undergo NMD

PM2

Not reported in gnomAD

PP4_Moderate

Tiranti et al 2004 and Tiranti et al 2006 report this patient with classic presentation of ethylmalonic encephalopathy with urinary ethylmalonic aciduria of 320 mg/g creatine (ref range <14.6 mg/g creatine). "All patients (in Tiranti et al 2004) had clinical and biochemical features typical of the disease"

PM3_Supporting

One single homozygote reported in multiple publications (Tiranti et al 2004 and 2006, Mineri et al 2008), confirmed through linkage analysis. Scored 0.5 per SVI PM3 guidance v1.0

PS3

Western blot was completed in Tiranti et al 2004, however, per VCEP guidelines ETHE1 persulfide dioxygenase is needed for PS3 supporting which was not performed

PP1

Only one case reported, two unaffected sibs. Insufficient to be scored for segregation

BA1

Not reported in gnomAD

BS1

Not reported in gnomAD

BS2

Not reported in gnomAD

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