ClinVar Miner

Submissions for variant NM_004453.4(ETFDH):c.1601C>T (p.Pro534Leu) (rs200920510)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483304 SCV000564970 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The P534L missense variant in the ETFDH gene has been reported previously in multiple patients in association with glutaric aciduria II (GAII) (Yotsumoto et al., 2008; Trakadis et al., 2012; Wolfe et al., 2010). The P534L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Molecular modeling of an ETFDH protein harboring the P534L variant predicts that this variant is within the iron sulfur cluster and is predicted to affect ubiquinone reductase activity of ETFDH and the docking of electrontransfer flavoprotein to ETFDH (Wolfe et al., 2010). In summary, we interpret the P534L variant to be a pathogenic variant.
Invitae RCV000818859 SCV000959493 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 534 of the ETFDH protein (p.Pro534Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs200920510, ExAC 0.004%). This variant has been observed in individuals with glutaric acidemia type 2 and was observed to segregate with disease in a family (PMID: 18289905, 21088898, 22664151). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 418184). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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