Submissions for variant NM_004092.4(ECHS1):c.88+5G>A

gnomAD frequency: 0.00001  dbSNP: rs761464256

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494412	SCV000583164	pathogenic	not provided	2022-06-15	criteria provided, single submitter	clinical testing	Functional studies found that this variant results in the insertion of 11 novel nucleotides, which introduces a premature termination codon and results in a 97% reduction in ECHS1 transcript level compared to controls (Al Mutairi et al., 2017); This variant is associated with the following publications: (PMID: 29882869, 28202214, 27905109, 31130284, 32552793)
Invitae	RCV000494412	SCV002263352	likely pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the ECHS1 gene. It does not directly change the encoded amino acid sequence of the ECHS1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. 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 been observed in individual(s) with clinical features of ECHS1-related conditions (PMID: 27905109, 36200804). ClinVar contains an entry for this variant (Variation ID: 430372). Studies have shown that this variant alters ECHS1 gene expression (PMID: 27905109). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in insertion of 11 nucleotides and introduces a premature termination codon (PMID: 27905109). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000656340	SCV004805021	pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2024-03-17	criteria provided, single submitter	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000656340	SCV000778303	uncertain significance	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2016-08-18	no assertion criteria provided	clinical testing