ClinVar Miner

Submissions for variant NM_004453.2(ETFDH):c.1367C>T (rs398124152)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081077 SCV000225342 pathogenic not provided 2012-08-20 criteria provided, single submitter clinical testing
GeneDx RCV000081077 SCV000238852 pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing p.Pro456Leu (CCG>CTG): c.1367 C>T in exon 11 of the ETFDH gene (NM_004453.2) The P456L missense mutation in the ETFDH gene has been reported previously in association with glutaric aciduria type II (Goodman et al., 2002). The variant is found in FAO-MET panel(s).
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081077 SCV000281023 pathogenic not provided 2015-06-10 criteria provided, single submitter clinical testing
Invitae RCV000174102 SCV000756263 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2019-09-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 456 of the ETFDH protein (p.Pro456Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs398124152, ExAC 0.01%). This variant has been reported as homozygous or in combination with another ETFDH variant in many individuals affected with multiple acyl-CoA dehydrogenase deficiency (PMID: 12359134, 23727839, 26403312, 17584774, 17412732). ClinVar contains an entry for this variant (Variation ID: 95072). Experimental studies have shown that this missense change causes misfolding, reduced thermal stability and lower binding affinity for co-enzyme Q10. Additionally, in fibroblasts from individuals with this variant, protein expression was reduced and decreased coenzyme Q10 levels were associated with increased levels of mitochondrial reactive oxygen species (PMID: 22611163, 23727839). Other missense substitutions at this codon (p.Pro456Ser, p.Pro456Thr) have been reported in individuals affected with multiple acyl-CoA dehydrogenase deficiency (PMID: 27038534, 16527485). This suggests that the proline residue is critical for ETFDH protein function. For these reasons, this variant has been classified as Pathogenic.

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