ClinVar Genomic variation as it relates to human health

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the ECHS1 protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ECHS1-related conditions (PMID: 25393721, 32677908, 33139125, 33163364). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 156434). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change alters ECHS1 gene expression (PMID: 25393721). For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect as A2V was associated with a reduction in protein expression and enzyme activity (Sakai et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25393721, 31967322, 33139125, 32677908, 33163364)

The ECHS1 c.5C>T; p.Ala2Val variant (rs587776498) is reported in the literature in the compound heterozygous state in several individuals affected with Leigh syndrome (Kuwajima 2021, Ogawa 2020, Sakai 2015, Sato-Shirai 2021, Stenton 2022, Sun 2020, Uesugi 2020, Yang 2022). This variant is also reported in ClinVar (Variation ID: 156434), but is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 2 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.604). However, functional analyses of the variant protein show decreased expression and enzyme activity (Sakai 2015). Based on available information, this variant is considered to be pathogenic. References: Kuwajima M et al. Valine metabolites analysis in ECHS1 deficiency. Mol Genet Metab Rep. 2021 Oct 9;29:100809. PMID: 34667719. Ogawa E et al. Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis. J Inherit Metab Dis. 2020 Jul;43(4):819-826. PMID: 31967322. Sakai C et al. ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. 2015 Feb;36(2):232-9. PMID: 25393721. Sato-Shirai I et al. Valine-restricted diet for patients with ECHS1 deficiency: Divergent clinical outcomes in two Japanese siblings. Brain Dev. 2021 Feb;43(2):308-313. PMID: 33139125. Stenton SL et al. Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital. Ann Neurol. 2022 Apr;91(4):466-482. PMID: 35094435. Sun D et al. Novel ECHS1 mutations in Leigh syndrome identified by whole-exome sequencing in five Chinese families: case report. BMC Med Genet. 2020 Jul 16;21(1):149. PMID: 32677908. Uesugi M et al. Short-chain enoyl-CoA hydratase deficiency causes prominent ketoacidosis with normal plasma lactate levels: A case report. Mol Genet Metab Rep. 2020 Oct 30;25:100672. PMID: 33163364. Yang Z et al. Whole-exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees. Am J Med Genet A. 2022 Apr;188(4):1214-1225. PMID: 35014173.

Converted during submission to Likely pathogenic.