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Variant: NM_014297.5(ETHE1):c.488G>A (p.Arg163Gln)

CA320215

214322 (ClinVar)

Gene: ETHE1
Condition: ethylmalonic encephalopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: 00257c9e-b540-4286-aa0e-f1a6c0e40cef
Approved on: 2021-07-27
Published on: 2021-07-27

HGVS expressions

NM_014297.5:c.488G>A
NM_014297.5(ETHE1):c.488G>A (p.Arg163Gln)
ENST00000292147.7:c.488G>A
ENST00000292147.6:c.488G>A
ENST00000594342.5:c.*51G>A
ENST00000598330.1:c.*51G>A
ENST00000600651.5:c.488G>A
NM_014297.3:c.488G>A
NM_001320867.1:c.455G>A
NM_001320868.1:c.119G>A
NM_001320869.1:c.194G>A
NM_014297.4:c.488G>A
NM_001320867.2:c.455G>A
NM_001320868.2:c.119G>A
NM_001320869.2:c.194G>A
NC_000019.10:g.43511454C>T
CM000681.2:g.43511454C>T
NC_000019.9:g.44015606C>T
CM000681.1:g.44015606C>T
NC_000019.8:g.48707446C>T
NG_008141.1:g.20791G>A

Pathogenic

Met criteria codes 5
PM5 PS3_Supporting PP4_Moderate PM3_Strong PP3
Not Met criteria codes 11
PM2 PM6 PVS1 BS1 BS2 BP5 BP2 BP4 PS2 PS1 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
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.
Met criteria codes
PM5
c.487C>T; p. R163W is a known pathogenic variant which meets the following criteria: PS3, PP1_strong, PM3_strong, PP4_moderate, PM5, PP3
PS3_Supporting
ETHE1 activity ~10% of WT
PP4_Moderate
Multiple patients reported in literature with developmental delay, diarrhea, petechiae, and acrocyanosis along with elevated EMA and elevated C4 w/ or w/o C5. Variant reported in Tiranti et al 2004 which defined the phenotype
PM3_Strong
Total Score = 2.0 -1.0 Patient L from PMID: 14732903; confirmed with VCEP that given cDNA testing completed it was reasonable to assume these variants were in trans given the truncating mutation is downstream of p.R163Q -0 PMID: 16183799; patient 5 not scored since homozygous w/o phase; patient 9 not scored to avoid circular logic with T136A (treated as a VUS) -0 Mineri et al. 2008; this is not the same patient as patient 9; patient 7 not scored to avoid circular logic with T136A -0.25 from PMID: 22020834;Proband confirmed in trans with VUS c.662_624del -0.25 from PMID: 27771676; in trans with LPath c.375+5G>T; treated as a VUS given single case reported -0.5 from PMID: 27391121; Homozygous via WES -0 from PMID: 30298498; Confirmed in trans with VUS c.2T>A; max of 0.5 for VUSs reached so not scored
PP3
Revel score is greater than 0.75
Not Met criteria codes
PM2
AF is 0.00005 in gnomAD, which is not <0.00002
PM6
No de novo cases reported
PVS1
Missense variant
BS1
AF is 0.00005 in gnomAD, which is not > >0.0002
BS2
Not seen in any homozygotes
BP5
No such case reported
BP2
No such case reported
BP4
Revel score is greater than 0.75
PS2
No de novo cases reported
PS1
No other mutations causing p.R163Q have been reported
BA1
BS1 not met
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