Submissions for variant NM_014297.5(ETHE1):c.586G>C (p.Asp196His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003476399	SCV004192689	likely pathogenic	Ethylmalonic encephalopathy	2023-08-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003476399	SCV004640873	likely pathogenic	Ethylmalonic encephalopathy	2023-06-15	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ethylmalonic encephalopathy (PMID: 32362910). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. This variant disrupts the p.Asp196 amino acid residue in ETHE1. Other variant(s) that disrupt this residue have been observed in individuals with ETHE1-related conditions (PMID: 18593870, 32362910), 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. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 196 of the ETHE1 protein (p.Asp196His).