Submissions for variant NM_014049.5(ACAD9):c.796C>T (p.Arg266Trp)

gnomAD frequency: 0.00002  dbSNP: rs753711253

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Medicine Lab, University of California San Francisco	RCV001007946	SCV001167659	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2019-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001582794	SCV001818534	likely pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 26669660, 33027564, 38243131, 30025539, 35723972)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001582794	SCV002233359	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg266 amino acid residue in ACAD9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21057504, 25721401, 30025539). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 242466). This missense change has been observed in individual(s) with clinical features of ACAD9-related conditions (PMID: 26669660, 33027564). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs753711253, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 266 of the ACAD9 protein (p.Arg266Trp).
MGZ Medical Genetics Center	RCV001007946	SCV002580866	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2022-06-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001007946	SCV002767273	pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 20 (MIM#611126). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, middle domain (Decipher). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The alternative change to a glutamine has been reported in individuals with complex I deficiency (PMID: 21057504). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with ACAD9 deficiency and complex I deficiency (ClinVar, PMID: 26669660). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional study using patient fibroblasts demonstrated reduced protein expression in ACAD9, ECSIT and NDUFAF1 (Brain and Mitochondrial lab, MCRI). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV001007946	SCV003826778	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2022-02-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001582794	SCV003916842	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ACAD9: PM2, PM3, PM5, PP3
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001007946	SCV004013994	pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2023-01-20	criteria provided, single submitter	clinical testing	PM5, PM2, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317172	SCV004021095	likely pathogenic	Mitochondrial complex I deficiency	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: ACAD9 c.796C>T (p.Arg266Trp) results in a non-conservative amino acid change in the encoded protein sequence, altering a well-conserved residue (HGMD) in which another missense variant is classified as pathogenic (ClinVar). 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 1.6e-05 in 251376 control chromosomes (gnomAD). c.796C>T has been reported in the literature in individuals affected with Mitochondrial Complex I Deficiency who were compound heterozygous with other likely pathogenic variants (Collet_2016, Sparks_2020). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26669660, 33027564). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001007946	SCV004209393	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2024-02-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001007946	SCV002081433	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2021-05-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755828	SCV005345108	likely pathogenic	ACAD9-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The ACAD9 c.796C>T variant is predicted to result in the amino acid substitution p.Arg266Trp. This variant has been reported in the compound heterozygous state in multiple patients with mitochondrial complex I deficiency, nuclear type 20 (Collet et al. 2016. PubMed ID: 26669660; Repp et al. 2018. PubMed ID: 30025539; Sparks et al. 2020. PubMed ID: 33027564). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.