Submissions for variant NM_014297.5(ETHE1):c.184G>A (p.Ala62Thr)

gnomAD frequency: 0.00019  dbSNP: rs138958351

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196829	SCV000251356	likely benign	not specified	2013-05-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000383149	SCV000413493	uncertain significance	Ethylmalonic encephalopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000383149	SCV000949911	likely benign	Ethylmalonic encephalopathy	2024-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517209	SCV003670212	uncertain significance	Inborn genetic diseases	2021-07-15	criteria provided, single submitter	clinical testing	The c.184G>A (p.A62T) alteration is located in exon 2 (coding exon 2) of the ETHE1 gene. This alteration results from a G to A substitution at nucleotide position 184, causing the alanine (A) at amino acid position 62 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196829	SCV004121759	uncertain significance	not specified	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: ETHE1 c.184G>A (p.Ala62Thr) results in a non-conservative amino acid change located in the Metallo-beta-lactamase (IPR001279) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 249992 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ETHE1 causing Ethylmalonic Encephalopathy (0.00032 vs 0.0013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.184G>A in individuals affected with Ethylmalonic Encephalopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Seelig Lab, University of Washington	RCV000767331	SCV000897901	not provided	not provided		no assertion provided	in vitro
Natera, Inc.	RCV000383149	SCV001456215	likely benign	Ethylmalonic encephalopathy	2020-06-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004757161	SCV005341169	likely benign	ETHE1-related disorder	2024-09-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).