ClinVar Genomic variation as it relates to human health

Two heterozygous variants were identified in the ECHS1 gene, NM_004092.3(ECHS1):c.518C>T and NM_004092.3(ECHS1):c.541C>T. The NM_004092.3(ECHS1):c.518C>T missense variant is in exon 5 of the ECHS1 gene (chr10:135180494). This substitution is predicted to create a change of an alanine to a valine at amino acid position 173, NP_004083.3(ECHS1):p.(Ala173Val), which is NOT considered significant. The alanine at this position has low conservation and therefore Grantham assessment (A-GVGD) is unlikely pathogenic. In silico software predictions of the pathogenicity of this variant are conflicting. It is situated within a known functional region (conserved trimeric quaternary structure which contains the catalytic core). This variant has not been previously observed in our patient cohort but it has been observed in a population database at a frequency of 0.04% (ExAC). It has been previously reported in a compound heterozygous state in three individuals presenting with later-onset movement disorders (Olgiati et al 2016, Mahajan et al 2017). Additional biochemical evaluation in this patient was consistent with ECHS1 deficiency. Based on current information and biochemical evidence, this variant has been classified as LIKELY PATHOGENIC.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the ECHS1 protein (p.Ala173Val). This variant is present in population databases (rs150321966, gnomAD 0.04%). This missense change has been observed in individual(s) with ECHS1-related conditions (PMID: 27090768, 28039521, 30008475, 32677093, 32858208). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 377257). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ECHS1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The observed missense variant c.518C>T(p.Ala173Val) in ECHS1 gene has been reported previously in compound heterozygous state in multiple individuals with ECHS1-related conditions (Illsinger S, et al., 2020, Olgiati S, et al., 2016). This variant is reported to being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The c.518C>T variant has 0.02% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic/Uncertain Significance. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid Alanine at position 173 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Ala173Val in ECHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31219693, 33931985, 32777769, 30008475, 28039521, 27090768, 29882869, 26099313, 31628766, 32858208, 33929620, 34140924, 34716721, 32677093, 33258288, 35856138, 35206276, 34052969, Das_2022_Abstract, 36200804, 35394834, 36883047, 33688149)

ECHS1: PM3:Strong, PM2, PP1

ACMG classification criteria: PM3 very strong, PP1 supporting