ClinVar Miner

Submissions for variant NM_014049.5(ACAD9):c.359del (p.Phe120fs)

dbSNP: rs863224844
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000779382 SCV000915988 likely pathogenic Acyl-CoA dehydrogenase 9 deficiency 2018-10-24 criteria provided, single submitter clinical testing The ACAD9 c.359delT (p.Phe120SerfsTer9) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has not been reported in the literature; however an equivalent variant, c.358delT (p.Phe120SerfsTer9) has been reported in at least five studies and is found in a compound heterozygous state in a total of three individuals with ACAD9 deficiency (Lee et al. 2014; Collet et al. 2015; Schiff et al. 2015; Fragaki et al. 2017; Repp et al. 2018). Control data are unavailable for the p.Phe120SerfsTer9 variant, which is reported at a frequency of 0.000527 in the Latino population of the Genome Aggregation Database. Mitochondrial respiratory chain complex I activity was reduced in patient-derived muscle and heart tissue (Collet et al. 2015; Schiff et al. 2015; Fragaki et al. 2017). Based on the evidence, the p.Phe120SerfsTer9 variant is classified as likely pathogenic for ACAD9 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV000813209 SCV000953554 pathogenic not provided 2024-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe120Serfs*9) in the ACAD9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAD9 are known to be pathogenic (PMID: 25721401). This variant is present in population databases (rs746304569, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with mitochondrial complex I deficiency (PMID: 25721401, 26669660, 28529009). This variant is also known as c.358delT. ClinVar contains an entry for this variant (Variation ID: 242524). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000813209 SCV001167849 pathogenic not provided 2022-04-30 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25721401, 28529009, 25326637, 31683770, 26669660, 30025539, 34440436, 34023438, 34204301)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282085 SCV002571761 pathogenic Mitochondrial complex I deficiency 2024-01-11 criteria provided, single submitter clinical testing Variant summary: ACAD9 c.359delT (p.Phe120SerfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0001 in 247292 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ACAD9 causing Mitochondrial Complex I Deficiency, Nuclear Type 20 (0.0001 vs 0.0011). c.359delT (also known as c.358delT) has been reported in the literature in individuals affected with Mitochondrial Complex I Deficiency and the variant segregated with disease (examples: Collet_2016, Fragaki_2017, Schiff_2015, and Barbosa-Gouveia_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34440436, 26669660, 28529009, 34023438, 25721401). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000779382 SCV002810928 pathogenic Acyl-CoA dehydrogenase 9 deficiency 2024-06-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV000779382 SCV004207119 pathogenic Acyl-CoA dehydrogenase 9 deficiency 2024-03-26 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000779382 SCV004234472 pathogenic Acyl-CoA dehydrogenase 9 deficiency 2023-03-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV000779382 SCV002081425 pathogenic Acyl-CoA dehydrogenase 9 deficiency 2020-08-17 no assertion criteria provided clinical testing

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