ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser) (rs545215807)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185742 SCV000238670 pathogenic not provided 2016-07-12 criteria provided, single submitter clinical testing The G185S variant has been previously reported in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency using an alternative numbering system based on the mature protein (G145S) (Andresen et al., 1999). An individual who was heterozygous for a single G185S mutation in VLCAD was found to have 29% residual VLCAD enzyme activity (Hoffmann et al. 2012).
Invitae RCV000412436 SCV000654958 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-07-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 185 of the ACADVL protein (p.Gly185Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs545215807, ExAC 0.01%). This variant has been reported in combination with other ACADVL variants in the fibroblasts from individuals affected with VLCADD (PMID: 17999356, 20060901). ClinVar contains an entry for this variant (Variation ID: 203595). Fibroblasts from affected individuals showed diminished VLCAD protein expression and enzyme activity (PMID: 17999356, 20060901). In addition, fibroblasts from an individual heterozygous of this variant has been shown to have 29% residual enzyme activity (PMID: 21932095). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the ACADVL gene (PMID: 20060901), suggest that this missense change is likely to be deleterious. However, these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change which has been observed in affected individuals and shown to disrupt protein expression and enzyme activity in patient fibroblasts. However, additional clinical or functional data are needed to fully substantiate the pathogenicity of this variant. Therefore, it has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000412436 SCV000883349 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-09-21 criteria provided, single submitter clinical testing The ACADVL c.553G>A; p.Gly185Ser variant (rs545215807), also known as Gly145Ser, has been reported in multiple individuals with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency when found with another pathogenic variant (Andresen 1999, Gobin-Limballe 2007, Yamaguchi 2012). Functional characterization of patient fibroblasts carrying this variant indicates a decrease in VLCAD protein levels (Andresen 1999, Gobin-Limballe 2010), resulting in significantly lower enzymatic activity compared to wildtype (Gobin-Limballe 2007, Hoffman 2012). The variant is listed in ClinVar (Variation ID: 203595), and observed twice in the Genome Aggregation Database (2/246250 alleles). The glycine at position 185 is highly conserved and is located in the substrate binding cavity (Hoffman 2012). Computational algorithms (PolyPhen-2, SIFT) predict that the p.Gly185Ser variant has an impact on ACADVL protein structure or function. Based on available information, this variant is considered 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; 64(2):479-94. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007; 81(6):1133-43. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010; 1802(5):478-84. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2):269-77. Yamaguchi S et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. Mol Genet Metab. 2012; 107(1-2):87-91.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000185742 SCV001246296 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000412436 SCV001364892 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.553G>A (NP_000009.1:p.Gly185Ser) [GRCH38: NC_000017.11:g.7221613G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Counsyl RCV000412436 SCV000485276 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-10-13 no assertion criteria provided clinical testing

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