ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.596C>T (p.Ala199Val)

gnomAD frequency: 0.00001  dbSNP: rs766579880
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761220 SCV000891174 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2017-12-15 criteria provided, single submitter clinical testing
Invitae RCV000761220 SCV000960558 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2023-06-30 criteria provided, single submitter clinical testing This variant is present in population databases (rs766579880, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 199 of the ACADS protein (p.Ala199Val). This missense change has been observed in individuals with clinical features of short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18523805, 28263315; Invitae). ClinVar contains an entry for this variant (Variation ID: 623120). 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 ACADS 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.
GeneDx RCV001551168 SCV001771617 likely pathogenic not provided 2020-07-13 criteria provided, single submitter clinical testing Reported in association with SCAD deficiency in individuals with failure to thrive, feeding difficulties and hypotonia who were compound heterozygous for the G209S variant (Pedersen et al., 2008); In vitro functional studies demonstrated A199V had a damaging effect on SCAD protein. Functional studies with complex allele including A199V and G209S caused a severe effect (Pedersen et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 28263315, 18523805)
Genome-Nilou Lab RCV000761220 SCV002033245 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-11-07 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003413549 SCV004114524 likely pathogenic ACADS-related condition 2023-07-25 criteria provided, single submitter clinical testing The ACADS c.596C>T variant is predicted to result in the amino acid substitution p.Ala199Val. This variant has been reported in patients with short chain acyl-coA dehydrogenase (SCAD) deficiency (Pedersen et al. 2008. PubMed ID: 18523805; Long et al. 2017. PubMed ID: 28263315). In experimental studies, the p.Ala199Val variant was shown to lead to defective tetramer formation and increased protein aggregation (Pedersen et al. 2008. PubMed ID: 18523805). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-121175763-C-T). This variant is interpreted as likely pathogenic.

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