Submissions for variant NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg)

gnomAD frequency: 0.00009  dbSNP: rs375032130

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432904	SCV000517223	pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28409271, 32800686, 26081110, 26099313, 26000322, 29575569, 29882869, 29923089, 32573669, 32329585, 32313153, 34426522, 33574353, 32677093, 35568357, 35098523)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578268	SCV000680203	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2017-11-16	criteria provided, single submitter	clinical testing
Kids Research, The Children's Hospital at Westmead	RCV000578268	SCV001244721	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency		criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000578268	SCV001244960	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2018-01-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_004092.3(ECHS1):c.476A>G, has been identified in exon 4 of 8 of the ECHS1 gene. The variant is predicted to result in a moderate amino acid change from glutamine to arginine at position 159 of the protein (NP_004083.3(ECHS1):p.(Gln159Arg)). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. The variant is present in the gnomAD database at a frequency of 0.01% (29 heterozygotes, 0 homozygotes). The variant has previously been reported as likely pathogenic in ClinVar and is reported multiple times in the liteature in patients with deficiency of shortchain enoyl-CoA hydratase (Ganetzky RD et al., 2016, Haack TB et al.; 2015, Tetreault M et al., 2015, Ferdinandusse S et al.; 2015). One of these reports showed significantly reduced enzymatic activity in a patient that was compound heterozygous for this variant (Ferdinandusse S et al.; 2015). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, Cologne University	RCV000578268	SCV001441222	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2020-09-30	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000578268	SCV002024457	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2020-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000432904	SCV002190789	pathogenic	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 159 of the ECHS1 protein (p.Gln159Arg). This variant is present in population databases (rs375032130, gnomAD 0.03%). This missense change has been observed in individual(s) with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (PMID: 26081110, 26099313, 28409271, 29575569). 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: 379794). 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 not expected to disrupt ECHS1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252122	SCV002522883	likely pathogenic	See cases	2021-02-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM2, PM3, PP1, PP4, BP4
CeGaT Center for Human Genetics Tuebingen	RCV000432904	SCV002821557	pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	ECHS1: PM3:Very Strong, PM2
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000578268	SCV004042689	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency		criteria provided, single submitter	clinical testing
OMIM	RCV000578268	SCV001422319	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2020-07-13	no assertion criteria provided	literature only