ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000185742 SCV000883349 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing
Counsyl RCV000412436 SCV000485276 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-10-13 criteria provided, single submitter clinical testing
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 2017-03-22 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.

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