Submissions for variant NM_000018.4(ACADVL):c.298_299del (p.Gln100fs)

dbSNP: rs786204713

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000169528	SCV002538672	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-03-08	reviewed by expert panel	curation	The c.298_299del p.(Gln100Valfs*3) variant in ACADVL is a deletion variant leading to a frameshift and is predicted to cause a premature stop codon in biologically-relevant-exon 5/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The variant has been identified in at least one individual with assertions of being clinically affected and follow-up plasma acylcarnitine analysis is consistent for very long chain acyl CoA dehydrogenase (VLCAD) deficiency without an additional ACADVL variant identified (PMID: 9973285). Reduced protein expression was reported in a heterozygous individual's cultured fibroblasts; RNA studies was not performed. However, this variant was not assessed in a non-patient derived cell line (PS3 at any strength is not met; PMID: 9973285). PM2_Supporting is met. 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 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. PP4, PM2_Supporting (ClinGen ACADVL VCEP specifications version2.0; date of approval: 02-08-2022)
Counsyl	RCV000169528	SCV000221005	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2015-01-06	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724267	SCV000230829	pathogenic	not provided	2014-09-08	criteria provided, single submitter	clinical testing
Invitae	RCV000169528	SCV000654949	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln100Valfs*3) 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 very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is also known as c.296_297del. ClinVar contains an entry for this variant (Variation ID: 189116). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169528	SCV003844579	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.298_299delCA (p.Gln100ValfsX3) 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 was absent in 251466 control chromosomes. c.298_299delCA has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1999, Zhang_2021, Zhang_2014, Li_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169528	SCV004215903	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000724267	SCV004224145	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	PP4, PM2_supporting, PVS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169528	SCV004564233	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-16	criteria provided, single submitter	clinical testing	The ACADVL c.298_299delCA; p.Gln100ValfsTer3 variant (rs786204713), also published as del296-97, is reported in the literature in an individual affected with VLCAD deficiency (Andresen 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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: Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. PMID: 9973285.