Submissions for variant NM_014297.5(ETHE1):c.494A>G (p.Asp165Gly)

gnomAD frequency: 0.00001  dbSNP: rs756235299

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501489	SCV000594598	likely pathogenic	Ethylmalonic encephalopathy	2016-08-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000523639	SCV000617485	likely pathogenic	not provided	2018-08-30	criteria provided, single submitter	clinical testing	The D165G variant in the ETHE1 gene has previously been reported as homozygous in an individual with ethylmalonic encephalopathy (Walsh et al., 2010). The D165G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D165G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R163W, R163Q, T164K) have been reported in the Human Gene Mutation Database in association with ethylmalonic encephalopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000501489	SCV002297259	likely pathogenic	Ethylmalonic encephalopathy	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 165 of the ETHE1 protein (p.Asp165Gly). This variant is present in population databases (rs756235299, gnomAD 0.002%). This missense change has been observed in individual(s) with ethylmalonic encephalopathy (PMID: 21472225). ClinVar contains an entry for this variant (Variation ID: 435094). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ETHE1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETHE1 function (PMID: 31477743). This variant disrupts the p.Asp165 amino acid residue in ETHE1. Other variant(s) that disrupt this residue have been observed in individuals with ETHE1-related conditions (PMID: 21472225, 32111695), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000501489	SCV004197150	likely pathogenic	Ethylmalonic encephalopathy	2024-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000501489	SCV005648347	likely pathogenic	Ethylmalonic encephalopathy	2024-03-06	criteria provided, single submitter	clinical testing