ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1376G>A (p.Arg459Gln) (rs751995154)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185726 SCV000238652 pathogenic not provided 2017-07-19 criteria provided, single submitter clinical testing The R459Qmissense variant in the ACADVL gene has been reported previously in multiple patients with VLCADdeficiency (Spiekerkoetter et al., 2003; Laforet et al. 2009; McGoey et al. 2011; Miller et al. 2015).R459Q is a semi-conservative amino acid substitution, it occurs at a position that is conserved acrossspecies, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. In summary, we interpret R459Q to be pathogenic.
Counsyl RCV000412089 SCV000487128 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-10-12 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414939 SCV000492896 likely pathogenic Myopathy; Rhabdomyolysis 2015-01-23 criteria provided, single submitter clinical testing
Invitae RCV000412089 SCV000654932 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 459 of the ACADVL protein (p.Arg459Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs751995154, ExAC 0.006%). This variant has been reported in individuals affected with VLCAD deficiency, several of them being clinically asymptomatic (PMID: 14517516, 23798014, 21429517, 19327992, 30194637). This variant is also known as p.Arg419Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 203585). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000412089 SCV000883346 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-03-20 criteria provided, single submitter clinical testing The ACADVL c.1376G>A; p.Arg459Gln variant (rs751995154), also known as p.Arg419Gln in traditional nomenclature, is reported in the literature in individuals with Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency (Laforet 2009, McGoey 2011, Miller 2015, Spiekerkoetter 2003, Waisbren 2013) and has been found in trans to other pathogenic variants (McGoey 2011, Spiekerkoetter 2003). Functional characterization of patient fibroblasts indicates significant reduction in VLCAD enzymatic activity (Laforet 2009). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 203585), and it is found on only eight chromosomes (8/282800 alleles) in the Genome Aggregation Database. The arginine at residue 459 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additional, another variant at the same codon (p.Arg459Trp) has been reported in individuals with VLCAD deficiency and is considered pathogenic (Andresen 1999, Miller 2015). Based on the above information, the p.Arg459Gln variant is considered to be pathogenic. References: Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009; 19(5):324-9. McGoey R et al. Positive newborn screen in a normal infant of a mother with asymptomatic very long-chain Acyl-CoA dehydrogenase deficiency. J Pediatr. 2011; 158(6):1031-2. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. Spiekerkoetter U et al. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2003; 143(3):335-42. Waisbren S et al. Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev. 2013; 17(3):260-8.
Fulgent Genetics,Fulgent Genetics RCV000412089 SCV000894149 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000412089 SCV001364928 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1376G>A (NP_000009.1:p.Arg459Gln) [GRCH38: NC_000017.11:g.7224011G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000412089 SCV001368576 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-04-02 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3.

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