ClinVar Miner

Submissions for variant NM_014297.5(ETHE1):c.505+1G>T

dbSNP: rs935855792
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV000598891 SCV001994847 pathogenic Ethylmalonic encephalopathy 2021-07-27 reviewed by expert panel curation The c.505+1G>T variant (NM_014297.5) in ETHE1 occurs within the canonical splice donor/acceptor site (+1) of exon/intron 4 boundary (exon 4/7). It is predicted to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 14732903). This prediction is supported by the absence of protein on Western blot of fibroblasts from patient J who was homozygous for this variant (PMID: 14732903). This variant is absent from gnomAD v2.1.1 (PM2). This variant was originally reported in a homozygote with developmental delay, petechiae, orthostatic acrocyanosis, chronic diarrhea, and ethylmalonic aciduria which is a phenotype highly specific to ethylmalonic encephalopathy (PP4_moderate; PMID: 14732903 patient J). While there are at least four homozygotes with ethylmalonic encephalopathy reported to date, parental linkage analyses have only been performed in one of these patients to confirm the variants were in trans (PM3_supporting; Total Score- 0.5; PMID: 14732903, PMID: 22584649, PMID: 18593870). 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): PVS1, PM2, PM3_supporting, PP4_Moderate. Approved 7/6/2021.
Revvity Omics, Revvity RCV000598891 SCV003821449 pathogenic Ethylmalonic encephalopathy 2022-05-31 criteria provided, single submitter clinical testing
OMIM RCV000598891 SCV000022570 pathogenic Ethylmalonic encephalopathy 2008-07-01 no assertion criteria provided literature only
GeneReviews RCV000598891 SCV000710834 not provided Ethylmalonic encephalopathy no assertion provided literature only

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