ClinVar Miner

Submissions for variant NM_004453.4(ETFDH):c.413T>G (p.Leu138Arg) (rs779896449)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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,Fulgent Genetics RCV000763115 SCV000893657 likely pathogenic Multiple acyl-CoA dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Integrated 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 likely pathogenic Multiple acyl-CoA dehydrogenase deficiency 2019-11-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 138 of the ETFDH protein (p.Leu138Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs779896449, ExAC 0.002%). This variant has been observed in individuals affected with multiple acyl-CoA dehydrogenase (PMID: 12359134, 15669683). ClinVar contains an entry for this variant (Variation ID: 431962). This variant has been reported to affect ETFDH protein function (PMID: 22611163). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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