Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV004586515 | SCV005077917 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2024-04-09 | reviewed by expert panel | curation | The c.1827+1G>A (NM_000018.4) variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 19. It is predicted to cause skipping of biologically-relevant-exon 19/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed a positive newborn screen followed by reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 30194637). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). |