Submissions for variant NM_004453.4(ETFDH):c.1414G>A (p.Gly472Arg)

gnomAD frequency: 0.00004  dbSNP: rs746598421

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554634	SCV000631955	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 472 of the ETFDH protein (p.Gly472Arg). This variant is present in population databases (rs746598421, gnomAD 0.03%). This missense change has been observed in individual(s) with multiple Acyl-CoA dehydrogenase deficiency (PMID: 12815589, 31268564; Invitae). ClinVar contains an entry for this variant (Variation ID: 459963). 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 ETFDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETFDH function (PMID: 12815589, 31268564). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000554634	SCV000891580	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-06-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000554634	SCV002548324	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: ETFDH c.1414G>A (p.Gly472Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251366 control chromosomes. c.1414G>A has been reported in the literature as a homozygous genotype in several individuals affected with Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (example, Olsen_2003, Ali_2021, van Rijt_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in homozygous individuals as measured by beta oxidation activity in whole fibroblast cells (Olsen_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000554634	SCV004194826	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV004592560	SCV005078241	likely pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.(G472R) significantly reduced protein expression and activity (PMID: 22611163); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 34573316, 31268564, 12815589, 22611163)
Natera, Inc.	RCV001834766	SCV002084872	pathogenic	Glutaric acidemia type 2C	2021-03-23	no assertion criteria provided	clinical testing