Submissions for variant NM_014049.5(ACAD9):c.1240C>A (p.Arg414Ser)

dbSNP: rs777282696

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002021912	SCV002231671	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 414 of the ACAD9 protein (p.Arg414Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 27233227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1451120). 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 ACAD9 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg414 amino acid residue in ACAD9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23836383, 27438479, 30025539). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004571697	SCV005052718	pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2023-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579582	SCV005062129	likely pathogenic	Mitochondrial complex I deficiency	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: ACAD9 c.1240C>A (p.Arg414Ser) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251388 control chromosomes (gnomAD). c.1240C>A has been reported in the literature in individuals affected with Mitochondrial Complex I Deficiency (Dewulf_2016). These data indicate that the variant may be associated with disease. Another missense variant affecting the same amino acid has been determined to be pathogenic, suggesting this is a functionally important residue. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27233227). ClinVar contains an entry for this variant (Variation ID: 1451120). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV004571697	SCV005659443	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2024-03-27	criteria provided, single submitter	clinical testing