ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1748C>G (p.Ser583Trp) (rs1085307648)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489971 SCV000576934 likely pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The S583W missense variant was previously identified in a 3-month-old with hypoketotichypoglycemia, hypotonia, hepatomegaly, elevated long chain acylcarnitine levels, and dicarboxylicaciduria in whom a second variant in ACADVL was not identified (Souri et al., 1998). The S583Wvariant has also been reported in individuals with positive newborn screens for very long chainacyl-CoA dehydrogenase (VLCAD) deficiency, although it is unknown if these individuals harboredanother ACADVL gene variant (Miller et al., 2015). Functional analyses found that S583W isassociated with impaired dimerization and 19% residual enzyme activity compared to wild type (Souriet al., 1998). The S583W variant is not observed in large population cohorts (Lek et al., 2016; 1000Genomes Consortium et al., 2015; Exome Variant Server). The S583W variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution occurs at a position that is conservedacross species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. In summary, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded.
Counsyl RCV000675075 SCV000800571 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-07-28 criteria provided, single submitter clinical testing
Invitae RCV000675075 SCV001205875 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-02-01 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 583 of the ACADVL protein (p.Ser583Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26385305, 9599005, 20480395). ClinVar contains an entry for this variant (Variation ID: 426482). This variant has been reported to affect ACADVL protein function (PMID: 9599005). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000675075 SCV001364940 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1748C>G (NP_000009.1:p.Ser583Trp) [GRCH38: NC_000017.11:g.7224711C>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9599005 . This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

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