Submissions for variant NM_014049.5(ACAD9):c.509C>T (p.Ala170Val)

gnomAD frequency: 0.00001  dbSNP: rs762521317

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001557392	SCV001779146	uncertain significance	not provided	2020-09-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30025539, 27233227, 28070495)
Invitae	RCV001557392	SCV002310875	likely pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the ACAD9 protein (p.Ala170Val). This variant is present in population databases (rs762521317, gnomAD 0.003%). This missense change has been observed in individual(s) with ACAD9-related conditions (PMID: 27233227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372249). 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 not expected to disrupt ACAD9 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.
MGZ Medical Genetics Center	RCV000412610	SCV002579676	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2022-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469142	SCV002766365	uncertain significance	not specified	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: ACAD9 c.509C>T (p.Ala170Val) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four 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 251434 control chromosomes (gnomAD). c.509C>T has been reported in the literature as a compound heterozygous genotype in two siblings affected with left ventricular hypertropy (Dewulf_2016), a presentation of Mitochondrial Complex I Deficiency, Nuclear Type 20. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27233227). Five ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000412610	SCV000490324	pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2018-12-13	no assertion criteria provided	literature only
Natera, Inc.	RCV000412610	SCV002081429	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2020-08-31	no assertion criteria provided	clinical testing