Submissions for variant NM_014049.5(ACAD9):c.1405C>T (p.Arg469Trp)

gnomAD frequency: 0.00042  dbSNP: rs139145143

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000488114	SCV000344763	uncertain significance	not provided	2016-08-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488114	SCV000575370	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ACAD9: PM2, PS3:Supporting
Fulgent Genetics, Fulgent Genetics	RCV000764463	SCV000895528	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000764463	SCV000915011	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2018-12-04	criteria provided, single submitter	clinical testing	The ACAD9 c.1405C>T (p.Arg469Trp) missense variant has been reported in one study in which it was identified in a compound heterozygous state with a second missense variant in one individual with mitochondrial complex I deficiency (Gerards et al. 2011). A muscle biopsy from the affected individual indicated a 91% reduction in mitochondrial complex 1 activity compared to control (Scholte et al. 1995). The p.Arg469Trp variant was absent from 233 controls and is reported at a frequency of 0.000744 in the European (non-Finnish) population of the Genome Aggregation Database. Recombinant Arg469Trp ACAD9 protein, derived from a bacterial expression system was stable and showed a mildly decreased enzyme activity compared to wild type (Schiff et al. 2015). Based on the evidence, the p.Arg469Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ACAD9 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000488114	SCV001574176	likely pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 469 of the ACAD9 protein (p.Arg469Trp). This variant is present in population databases (rs139145143, gnomAD 0.07%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 20929961, 30025539; Invitae). ClinVar contains an entry for this variant (Variation ID: 214007). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACAD9 function (PMID: 25721401). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155116	SCV003844647	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: ACAD9 c.1405C>T (p.Arg469Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 251318 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACAD9 causing Mitochondrial Complex I Deficiency, Nuclear Type 20 (0.0004 vs 0.0011), allowing no conclusion about variant significance. c.1405C>T has been reported in the literature in individuals affected with Mitochondrial Complex I Deficiency, Nuclear Type 20. These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial Complex I Deficiency, Nuclear Type 20. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant effect results in about 80% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=5, likely pathogenic n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000764463	SCV004207052	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2023-10-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000488114	SCV000802485	uncertain significance	not provided	2016-02-26	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000488114	SCV001743125	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488114	SCV001966917	likely benign	not provided		no assertion criteria provided	clinical testing