Submissions for variant NM_000018.4(ACADVL):c.104del (p.Pro35fs)

dbSNP: rs1443151475

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000652036	SCV002538677	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-04-06	reviewed by expert panel	curation	The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 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 at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID: 25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021).
Invitae	RCV000652036	SCV000773897	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro35Leufs*26) 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 present in population databases (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 25834949). ClinVar contains an entry for this variant (Variation ID: 541718). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000652036	SCV001364883	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.104delC (NP_000009.1:p.Pro35LeufsTer26) [GRCH38: NC_000017.11:g.7220163delC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 25834949 . This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000652036	SCV001623415	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-05-06	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.104delC (p.Pro35LeufsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.2e-05 in 137290 control chromosomes. c.104delC has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1999, Knottnerus_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports that enzyme activity in the patient carrying homozygous c.104delC had <10% of normal activity (Knottnerus_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.