Submissions for variant NM_004092.4(ECHS1):c.414+1G>A

gnomAD frequency: 0.00001  dbSNP: rs754815893

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089955	SCV001244959	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency	2018-01-28	criteria provided, single submitter	clinical testing	A heterozygous canonical splice-site variant, NM_004092.3(ECHS1):c.414+1G>A, has been identified in intron 3 of 8 of the ECHS1 gene. The variant is likely to cause a splice defect, resulting in altered protein length. The nucleotide at this position has very high conservation (Phylop UCSC). Loss of protein function is predicted either through truncation (although no known functional domains are affected), which is a reported mechanism of pathogenicity for this gene, or nonsense-mediated decay. Further testing via RNA studies is required to confirm if and how splicing is altered. The variant is present in the gnomAD database at a frequency of 0.0016% (4 heterozygotes, no homozygotes). It has not been previously reported in clinical cases. However, a different variant in the same splice region (c.414+3) has previously been reported in trans with a missense variant in two siblings with deficiency of shortchain enoyl-CoA hydratase. Functional studies showed significantly reduced enzymatic activity and altered splicing, resulting in an inframe deletion of amino acids 126 to 138 (Peters H. et al., 2014). Subsequent analysis of parental samples for this case indicated the c.414+1G>A variant was paternally inherited. Based on the information available at the time of curation, and in combination with the pathogenic maternally inherited compound heterozygous p.(Gln159Arg) missense variant, this variant has been classified as LIKELY PATHOGENIC.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001089955	SCV002820312	likely pathogenic	Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency		criteria provided, single submitter	clinical testing	The splice donor variant c.414+1G>A in ECHS1 (NM_004092.4) has been reported to ClinVar as Likely Pathogenic. The c.414+1G>A variant is observed in 2/16,222 (0.0123%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant mutates a splice-donor sequence, potentially resulting in the retention of large segments of intronic DNA by the mRNA and nonfunctional proteins. The c.414+1G>A variant is a loss of function variant in the gene ECHS1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant. For these reasons, this variant has been classified as Likely Pathogenic.