Submissions for variant NM_014049.5(ACAD9):c.1832A>G (p.Tyr611Cys)

gnomAD frequency: 0.00003  dbSNP: rs1057523761

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418959	SCV000533234	uncertain significance	not provided	2021-06-07	criteria provided, single submitter	clinical testing	Identified by whole exome sequencing in the presence of a second ACAD9 variant in an infant presenting prenatally with lissencephalopathy, agenesis of the corpus callosum, intrauterine growth restriction and cardiomyopathy with approximately 20% ACAD9 protein level by Western blot analysis but nearly normal complex I activity (Repp et al., 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 27535533, 30025539)
Illumina Laboratory Services, Illumina	RCV001147005	SCV001307772	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584121	SCV001821297	uncertain significance	not specified	2021-08-05	criteria provided, single submitter	clinical testing	Variant summary: ACAD9 c.1832A>G (p.Tyr611Cys) results in a non-conservative amino acid change in 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 8e-06 in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1832A>G has been reported in the literature in one individual affected with ACAD9 deficiency. This report does not provide unequivocal conclusions about association of the variant with Mitochondrial Complex I Deficiency, Nuclear Type 20. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000418959	SCV003521207	uncertain significance	not provided	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 611 of the ACAD9 protein (p.Tyr611Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with ACAD9-related conditions (PMID: 30025539, 32746448). ClinVar contains an entry for this variant (Variation ID: 390412). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV001147005	SCV003822443	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2022-10-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001147005	SCV004207041	likely pathogenic	Acyl-CoA dehydrogenase 9 deficiency	2023-11-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001147005	SCV002081456	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2020-02-18	no assertion criteria provided	clinical testing