Submissions for variant NM_014297.5(ETHE1):c.476G>A (p.Arg159His)

gnomAD frequency: 0.00003  dbSNP: rs768669208

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199428	SCV000251360	likely pathogenic	not provided	2014-06-16	criteria provided, single submitter	clinical testing	p.Arg159His (CGT>CAT): c.476 G>A in exon 4 of the ETHE1 gene (NM_014297.3). A R159H variant that is likely pathogenic was identified in the ETHE1 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R159H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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 mutations in nearby residues (T164K, R163Q, R163G, R163W, C161Y, and T152I) have been reported in association with ethylmalonic encephalopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Invitae	RCV000814742	SCV000955164	uncertain significance	Ethylmalonic encephalopathy	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 159 of the ETHE1 protein (p.Arg159His). This variant is present in population databases (rs768669208, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ETHE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 214321). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000199428	SCV001151946	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing