Submissions for variant NM_000018.4(ACADVL):c.1803G>A (p.Met601Ile)

gnomAD frequency: 0.00009  dbSNP: rs201462718

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414590	SCV000492029	uncertain significance	not specified	2016-11-18	criteria provided, single submitter	clinical testing	The M601I variant in the ACADVL gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M601I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M601I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (E599K, L602I) have been reported in the Human Gene Mutation Database in association with VLCAD deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret M601I as a variant of uncertain significance,
Invitae	RCV001047994	SCV001211983	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 601 of the ACADVL protein (p.Met601Ile). This variant is present in population databases (rs201462718, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. ClinVar contains an entry for this variant (Variation ID: 373437). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Illumina Laboratory Services, Illumina	RCV001047994	SCV001282892	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001047994	SCV001365128	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1803G>A (NP_000009.1:p.Met601Ile) [GRCH38: NC_000017.11:g.7224860G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM1, PM3, PP4
CeGaT Center for Human Genetics Tuebingen	RCV002275021	SCV002563379	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	ACADVL: PM2, PP4
Natera, Inc.	RCV001047994	SCV001459266	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing