ClinVar Miner

Submissions for variant NM_004092.4(ECHS1):c.72G>A (p.Trp24Ter)

gnomAD frequency: 0.00001  dbSNP: rs776926045
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001267694 SCV001445943 uncertain significance Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency 2020-11-16 criteria provided, single submitter curation The heterozygous p.Trp24Ter variant in ECHS1 was identified by our study in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with mitochondrial short-chain enoyl-coa hydratase 1 deficiency. The variant has not been previously reported in individuals with mitochondrial short-chain enoyl-coa hydratase 1 deficiency and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 24, which is predicted to lead to a truncated or absent protein. While there is some evidence to suggest that loss of function of the ECHS1 gene is a disease mechanism in autosomal recessive mitochondrial short-chain enoyl-coa hydratase 1 deficiency, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PVS1_moderate (Richards 2015).
Baylor Genetics RCV001267694 SCV003835640 pathogenic Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency 2021-02-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003770398 SCV004641024 pathogenic not provided 2023-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp24*) in the ECHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ECHS1 are known to be pathogenic (PMID: 25393721, 26000322, 27090768). 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 variant has not been reported in the literature in individuals affected with ECHS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 986371). For these reasons, this variant has been classified as Pathogenic.

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