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.