Submissions for variant NM_014049.5(ACAD9):c.442A>G (p.Ile148Val)

gnomAD frequency: 0.00011  dbSNP: rs202119704

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196891	SCV000251021	uncertain significance	not provided	2017-06-20	criteria provided, single submitter	clinical testing	p.Ile148Val (ATT>GTT): c.442 A>G in exon 4 of the ACAD9 gene (NM_014049.4). The I148V missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is conservative in that both Isoleucine and Valine are uncharged, non-polar amino acids. This change occurs at a highly conserved position in the ACAD9 protein. In-silico analyses predict that I148V is damaging to the ACAD9 protein. Therefore, based on the currently available information, it is unclear whether I148V is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV000329932	SCV000440757	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2018-01-13	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.
Invitae	RCV000196891	SCV003282376	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 148 of the ACAD9 protein (p.Ile148Val). This variant is present in population databases (rs202119704, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ACAD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 213995). 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.
Natera, Inc.	RCV000329932	SCV001460354	uncertain significance	Acyl-CoA dehydrogenase 9 deficiency	2020-04-23	no assertion criteria provided	clinical testing