Submissions for variant NM_004092.4(ECHS1):c.176A>G (p.Asn59Ser)

gnomAD frequency: 0.00001  dbSNP: rs201865375

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387132	SCV001587676	pathogenic	not provided	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 59 of the ECHS1 protein (p.Asn59Ser). This variant is present in population databases (rs201865375, gnomAD 0.02%). This missense change has been observed in individuals with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (PMID: 26000322, 26251176, 28429146). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218890). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ECHS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ECHS1 function (PMID: 26251176). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000203238	SCV002012338	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID:VCV000218890.5, PMID:28429146, 26251176, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000036, PM2). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous in at least one similarly affected unrelated individual (PMID:28429146, 26251176; 3billion dataset). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.712, 3Cnet: 0.973, PP3). Patient's phenotype is considered compatible with Mitochondrial Short-Chain Enoyl-CoA Hydratase Deficiency (3billion dataset, PP4). Therefore, this variant is classified aslikely pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000203238	SCV002024451	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2020-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001387132	SCV002567428	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that N59S results in an unstable ECHS1 protein (Yamada et al., 2015); 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: 31967322, 31016024, 33163364, 26000322, 32013919, 33139125, 28429146, 34426522, 34667719, 33574353, 32901917, 26251176)
OMIM	RCV000203238	SCV000258305	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2015-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748657	SCV005344573	pathogenic	ECHS1-related disorder	2024-07-07	no assertion criteria provided	clinical testing	The ECHS1 c.176A>G variant is predicted to result in the amino acid substitution p.Asn59Ser. This variant has been reported in the compound heterozygous state in multiple individuals with ECHS1-deficiency (see for example, Haack et al. 2015. PubMed ID: 26000322; Supplemental Table, Ogawa et al. 2020. PubMed ID: 31967322; Kuwajima et al. 2021. PubMed ID: 34667719). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD, and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/218890/). Given the evidence, we interpret this variant as pathogenic.