Submissions for variant NM_000018.4(ACADVL):c.1818G>A (p.Trp606Ter)

dbSNP: rs2071404265

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001200790	SCV003936889	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-27	reviewed by expert panel	curation	The c.1818G>A (p.Trp606Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported once as a result of a positive newborn screening for VLCADD (PMID:26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as VUS based on PVS1_Moderate+PM2_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200790	SCV001364991	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1818G>A (NP_000009.1:p.Trp606Ter) [GRCH38: NC_000017.11:g.7224875G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Invitae	RCV001200790	SCV003442483	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp606*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the ACADVL protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Arg615*) have been determined to be pathogenic (PMID: 10431122). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 932836). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305). This variant is not present in population databases (gnomAD no frequency).