ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.538G>A (p.Ala180Thr) (rs727503791)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000152735 SCV000202122 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing
GeneDx RCV000152735 SCV000238635 pathogenic not provided 2015-03-26 criteria provided, single submitter clinical testing The A180T missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It has been seen previously at GeneDx in multiple patients referred for analysis of the ACADVL gene. One such patient also harbored a previously reported disease-associated ACADVL missense mutation. A180T is a nonconservative amino acid change in that a hydrophobic amino acid, Alanine, is replaced by a hydrophilic amino acid, Threonine. This missense change occurs at a highly conserved position in the ACADVL protein across species and in other acyl-CoA dehydrogenases. Multiple missense mutations at nearby positions (V174M, L178P, G179W, G185W, G185S, I189T) have been reported in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and multiple in-silico analysis programs predict that A180T is damaging to the ACADVL protein. Therefore, we interpret A180T to be a pathogenic mutation.The variant is found in ACADVL panel(s).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000675106 SCV000602371 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-11-13 criteria provided, single submitter clinical testing The ACADVL c.538G>A; p.Ala180Thr variant (rs727503791) is reported in the literature to be significantly enriched in patients with abnormal newborn screening results suggestive of VLCAD deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 166641), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at residue 180 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ala180Thr variant is considered to be likely pathogenic. References: Miller M 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; 116(3):139-45.
Counsyl RCV000675106 SCV000800653 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-01-16 criteria provided, single submitter clinical testing
Invitae RCV000675106 SCV001233673 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 180 of the ACADVL protein (p.Ala180Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs727503791, ExAC 0.009%). This variant has been observed in individuals with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 30194637) and in an individual with a positive newborn screening result for ACADVL-related disease (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 166641). 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. 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000675106 SCV001365220 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.538G>A (NP_000009.1:p.Ala180Thr) [GRCH38: NC_000017.11:g.7221598G>A] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3

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