Submissions for variant NM_000018.4(ACADVL):c.1807dup (p.Cys603fs)

gnomAD frequency: 0.00001  dbSNP: rs1555529088

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001069851	SCV002769782	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-14	reviewed by expert panel	curation	The c.1807dup (p.Cys603fs) variant in ACADVL, also known as p.Cys603LeufsTer2, is a frameshift 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). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 27590926). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021).
GeneDx	RCV000483312	SCV000565952	pathogenic	not provided	2022-08-24	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32746448)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069851	SCV001235048	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys603Leufs*2) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the ACADVL protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. ClinVar contains an entry for this variant (Variation ID: 418698). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001069851	SCV001364990	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1807dupT (NP_000009.1:p.Cys603LeufsTer2) [GRCH38: NC_000017.11:g.7224864dup] 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
Baylor Genetics	RCV001069851	SCV004212670	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001069851	SCV001459267	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing