Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000498882 | SCV000589571 | pathogenic | not provided | 2017-05-23 | criteria provided, single submitter | clinical testing | The L138R missense variant in the ETFDH gene has been reported previously in association with glutaric aciduria II (GAII) (Olsen et al. 2004; Cornelius et al. 2012; Goodman et al. 2002). Expression studies show that L138R profoundly reduces the amount and activity of the electron transfer flavoprotein-ubiquinone oxidoreductase enzyme with no significant response to increasing concentrations of riboflavin (Cornelius et al. 2012). The L138R 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 L138R 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret L138R to be a pathogenic variant. |
Fulgent Genetics, |
RCV000763115 | SCV000893657 | likely pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2021-07-29 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000763115 | SCV001360939 | pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2019-10-14 | criteria provided, single submitter | clinical testing | Variant summary: ETFDH c.413T>G (p.Leu138Arg) 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 8e-06 in 250696 control chromosomes (gnomAD). c.413T>G has been reported in the literature in individuals affected with Glutaric aciduria, type 2 (Goodman_2002, Olsen_2004, Cornelius_2012). These data indicate that the variant may be associated with disease. A functional study, Cornelius_2012, found the variant to impact enzyme activity and protein stability. Two ClinVar submissions (evaluation after 2014) cite the variant once as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV000763115 | SCV001377643 | pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 138 of the ETFDH protein (p.Leu138Arg). This variant is present in population databases (rs779896449, gnomAD 0.002%). This missense change has been observed in individuals with multiple acyl-CoA dehydrogenase (PMID: 12359134, 15669683, 32925727). ClinVar contains an entry for this variant (Variation ID: 431962). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ETFDH protein function. Experimental studies have shown that this missense change affects ETFDH function (PMID: 22611163). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV001266160 | SCV001444332 | pathogenic | Inborn genetic diseases | 2018-01-24 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000763115 | SCV004194781 | pathogenic | Multiple acyl-CoA dehydrogenase deficiency | 2023-09-29 | criteria provided, single submitter | clinical testing |