ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.520G>A (p.Val174Met) (rs369560930)

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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 RCV000077919 SCV000231986 pathogenic not provided 2015-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000077919 SCV000518399 likely pathogenic not provided 2017-09-26 criteria provided, single submitter clinical testing The V174M missense variant has been previously reported in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Tajima et al., 2008; Gobin-Limballe et al., 2010; Andresen et al., 1999). V174M is reported to likely be a mild ACADVL variant as fibroblasts homozygous for V174M showed enzyme activity equivalent to 27% of normal levels (Gobin-Limballe et al., 2010). The V174M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V174M substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, we interpret V174M as likely pathogenic.
Invitae RCV000179696 SCV000773888 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 174 of the ACADVL protein (p.Val174Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs369560930, ExAC 0.01%). This variant has been reported as homozygous or in combination with another ACADVL variant in several individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 17999356, 18670371, 23430950, 26881790). This variant is also known as p.Val134Met in the literature.  ClinVar contains an entry for this variant (Variation ID: 92286). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000077919 SCV000883332 pathogenic not provided 2018-04-02 criteria provided, single submitter clinical testing The ACADVL c.520G>A; p.Val174Met variant (rs369560930), also known as Val134Met, has been identified in individuals with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, who are compound heterozygous or homozygous carriers (Andresen 1999, Diekman 2016, Gobin-Limballe 2010, Tajima 2008). It is reported as likely pathogenic and pathogenic in ClinVar (Variation ID: 92286) and is observed in the general population at a low overall frequency of 0.006% (17/277192) in the Genome Aggregation Database. The valine at codon 174 is moderately conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious. Additionally, functional studies of a patient’s fibroblasts with homozygous p.Val174Met demonstrated FAO capacities that were 27% of the normal level (Gobin-Limballe 2010). 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 Feb;64(2):479-94. Diekman E et al. Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. PLoS One. 2016 Feb 16;11(2):e0147818. 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 May;1802(5):478-84. Tajima G et al. Development of a new enzymatic diagnosis method for very-long-chain Acyl-CoA dehydrogenase deficiency by detecting 2-hexadecenoyl-CoA production and its application in tandem mass spectrometry-based selective screening and newborn screening in Japan. Pediatr Res. 2008 Dec;64(6):667-72.
Baylor Genetics RCV000179696 SCV001163797 pathogenic Very long chain acyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Counsyl RCV000179696 SCV000486666 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-07-21 no assertion criteria provided clinical testing

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