Submissions for variant NM_000018.4(ACADVL):c.1882del (p.Gln628fs)

dbSNP: rs1597541142

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001001435	SCV003936867	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-27	reviewed by expert panel	curation	The c.1882del (p.Gln628LysfsTer52) variant in ACADVL is a frameshift in the last exon of a gene in which loss-of-function is an established disease mechanism (PVS1_moderate: PMIDs 9973285, 11590124). While this may not lead to nonsense-mediated decay, this variant is predicted to replace the final 28 conserved amino acids in ACADVL with functional significance (PMID: 18227065). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as VUS based on PVS1_moderate+PM2_supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001435	SCV001158672	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-03-21	criteria provided, single submitter	clinical testing	The ACADVL c.1882delC; p.Gln628fs variant (rs371091547), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a frameshift in the last exon of the ACADVL gene. While this may not lead to nonsense-mediated decay, it is expected to create a protein that would include a sequence of 52 amino acid residues in place of the final 28 canonical amino acids. Supporting the notion that this variant is deleterious, frameshift variants downstream of the p.Gln628fs variant have been reported in individuals with VLCAD deficiency and are considered pathogenic (Gobin-Limballe 2010, Miller 2015). Based on available information, the p.Gln628fs variant is considered to be likely pathogenic. References: Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. 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.
Invitae	RCV001001435	SCV001215529	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the ACADVL gene (p.Gln628Lysfs*52). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the ACADVL protein and extend the protein by 23 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 811520). This variant results in an extension of the ACADVL protein. Other variant(s) that result in a similarly extended protein product (p.Ala640Trpfs*39) have been observed in individuals with ACADVL-related disease (PMID: 17999356). This suggests that these extensions may be clinically significant. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001001435	SCV001361317	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-06-02	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1882delC (p.Gln628LysfsX52) causes a frameshift which results in an extension of the protein. The variant was absent in 251310 control chromosomes. To our knowledge, no occurrence of c.1882delC in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, other variants causing an extension of the protein have been reported as pathogenic in ClinVar and HGMD. Based on the evidence outlined above, the variant was classified as likely pathogenic.