ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1019G>T (p.Gly340Val) (rs934797393)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489813 SCV000576556 likely pathogenic not provided 2017-04-27 criteria provided, single submitter clinical testing The G340V variant has been reported in multiple patients with abnormal newborn screening results for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in whom a second variant was not identified in the ACADVL gene (Miller et al. 2015). The G340V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G340V variant is a conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant at the same position (G340E) has also 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. In summary, we interpret G340V as likely pathogenic.
Invitae RCV000555492 SCV000654915 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 340 of the ACADVL protein (p.Gly340Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as heterozygous or in combination with another ACADVL variant in individuals suspected with VLCAD deficiency by newborn screening (PMID: 26385305, 27246109). ClinVar contains an entry for this variant (Variation ID: 415586). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on ACADVL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000555492 SCV000800660 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-02-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000489813 SCV000884953 likely pathogenic not provided 2017-07-27 criteria provided, single submitter clinical testing The ACADVL c.1019G>T;p.Gly340Val variant has been described in the medical literature in individuals identified by newborn screen and at least one reportedly symptomatic adult (Evans 2016, Miller 2015, Olpin 2017). The variant is listed in the ClinVar database (Variation ID: 426177) but not the dbSNP variant database or the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species, located near the active site (McAndrew 2008), and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is considered likely pathogenic. References: Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. 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. Olpin SE et al. Fibroblast Fatty-Acid Oxidation Flux Assays Stratify Risk in Newborns with Presumptive-Positive Results on Screening for Very-Long Chain Acyl-CoA Dehydrogenase Deficiency. Int J Neonat Screen. 2017 3(1):2.

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