ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1748C>T (p.Ser583Leu)

gnomAD frequency: 0.00001  dbSNP: rs1085307648
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665031 SCV000789086 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2017-01-06 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000665031 SCV001364941 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1748C>T (NP_000009.1:p.Ser583Leu) [GRCH38: NC_000017.11:g.7224711C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 15210884. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000665031 SCV001472293 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-09-19 criteria provided, single submitter clinical testing The ACADVL c.1748C>T; p.Ser583Leu variant (rs1085307648) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency, some of whom had significantly lower VLCAD enzyme activity (Bujan 2014, Campbell 2005, Miller 2015, Ohashi 2004). This variant is reported in ClinVar (Variation ID: 550315), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 583 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1748C>G; p.Ser583Trp) has been reported in individuals with VLCAD deficiency (Miller 2015). Based on available information, this variant is considered to be pathogenic. References: Bujan N et al. Characterization of CoQ10 biosynthesis in fibroblasts of patients with primary and secondary CoQ10 deficiency. J Inherit Metab Dis. 2014 Jan;37(1):53-62. Campbell CD et al. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica. 2005 Dec;90(12 Suppl):ECR45. 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. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13.
Invitae RCV000665031 SCV002309913 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-11-07 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 583 of the ACADVL protein (p.Ser583Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 15210884, 16464760, 23774949). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as S543L. ClinVar contains an entry for this variant (Variation ID: 550315). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.