The c.505+1G>A 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). There is another pathogenic variant at this position (c.505+1G>T) for which Western blot analyses provided supportive evidence for nonsense mediated decay (PMID: 14732903). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (2/251,460 alleles) in the general population, which is lower than the ClinGen ETHE1 threshold < 0.00002 for PM2, meeting this criterion (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 O). While there are at least 2 homozygotes of this variant with ethylmalonic encephalopathy reported to date, parental analyses have only been performed in one of these patients to confirm the variants were in trans (PM3_supporting; PMID: 29526615). 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.