ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 456 of the ETFDH protein (p.Pro456Leu). This variant is present in population databases (rs398124152, gnomAD 0.007%). This missense change has been observed in individuals with multiple acyl-CoA dehydrogenase deficiency (PMID: 12359134, 17412732, 17584774, 23727839, 26403312). ClinVar contains an entry for this variant (Variation ID: 95072). 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, 23727839). This variant disrupts the p.Pro456 amino acid residue in ETFDH. Other variant(s) that disrupt this residue have been observed in individuals with ETFDH-related conditions (PMID: 17412732, 17584774, 23727839, 26403312, 27038534), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Variant summary: ETFDH c.1367C>T (p.Pro456Leu) 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 4.4e-05 in 251324 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ETFDH causing Glutaric Aciduria, Type 2c (4.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.1367C>T has been reported in the literature as a homozygous/compound heterozygous genotype in multiple individuals affected with Riboflavin responsive Glutaric Aciduria, Type 2c (example, Goodman_2002, Olsen_2007). 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 (Cornelius_2013). The most pronounced variant effect results in impaired thermal stability and increased reactive oxygen species in an HEK-293 in-vitro system. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate a reduction in enzyme activity compared to wildtype, supporting a damaging effect (Cornelius et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18836889, 22611163, 23727839, 12359134, 26403312, 17412732, 22190129, 19265687, 18289905, 23052622, 17584774, 32087359, 31904027, 36406819)