ClinVar Miner

Submissions for variant NM_004092.4(ECHS1):c.476A>G (p.Gln159Arg) (rs375032130)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432904 SCV000517223 likely pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing The Q159R variant has been reported previously in several individuals with features of an ECHS1-related disorder (Tetreault et al., 2015; Haack et al., 2015; Ferdinandusse et al., 2015). The Q159R variant is observed in 9/30,778 (0.03%) alleles from individuals of South Asian background, in the ExAC dataset (Lek et al., 2016). The Q159R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, we interpret this variant as likely pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar 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.
OMIM RCV000578268 SCV001422319 pathogenic Mitochondrial short-chain enoyl-coa hydratase 1 deficiency 2020-07-13 no assertion criteria provided literature only

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