Submissions for variant NM_000018.4(ACADVL):c.1039del (p.Ala347fs)

dbSNP: rs2071295244

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001200805	SCV002576737	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-22	reviewed by expert panel	curation	The c.1039del (p.Ala347Profs*6) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). This variant has been detected in one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity; a second distinct pathogenic or likely pathogenic variant in ACADVL was not reported in this individual (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC 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, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 07-03-2022).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200805	SCV001364971	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1039delG (NP_000009.1:p.Ala347ProfsTer6) [GRCH38: NC_000017.11:g.7222827del] 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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001200805	SCV002506158	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-12-14	criteria provided, single submitter	clinical testing	The ACADVL c.1039delG; p.Ala347ProfsTer6 variant (rs2071295244) is reported in the literature in an infant with a positive newborn screen (Miller 2015). This variant is reported in ClinVar (Variation ID: 932848) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200805	SCV004296680	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.Ala347Profs*6) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ACADVL-related conditions (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 932848). For these reasons, this variant has been classified as Pathogenic.