ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1096C>T (p.Arg366Cys) (rs771874163)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185719 SCV000238644 pathogenic not provided 2015-03-23 criteria provided, single submitter clinical testing The R366C missense mutation identified in the ACADVL gene has been reported previously in association with VLCAD deficiency (Andresen et al., 1996). The variant is found in ACADVL panel(s).
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185719 SCV000281260 pathogenic not provided 2014-05-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000675110 SCV000602375 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-09-20 criteria provided, single submitter clinical testing The ACADVL c.1096C>T; p.Arg366Cys variant (rs771874163), also known as p.Arg326Cys, is reported in the literature in individuals affected with VLCAD deficiency (Andresen 1996, Andresen 1999, Hoffman 2012). Analysis of enzymatic palmitoyl-CoA dehydrogenase activity in affected individuals indicates that the variant protein has reduced activity compared to wildtype, with individuals showing residual activity less than 50 percent in fibroblasts (Andresen 1996) or lymphocytes (Hoffman 2012, Spiekerkoetter 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 203579) and is found in the general population with an overall allele frequency of 0.002% (5/246272 alleles) in the Genome Aggregation Database. An additional variant at this codon (c.1097G>A, p.Arg366His) has been reported in individuals with VLCAD deficiency and is considered pathogenic (Andresen 1999, Gobin-Limballe 2010). The arginine at codon 366 is highly conserved and forms a salt bridge with the FAD cofactor in the neighboring subunit of an ACADVL dimer, thus promoting both FAD binding and association of enzyme monomers (Gobin-Limballe 2010, Hoffman 2012, McAndrew 2008). Computational analyses (SIFT, PolyPhen-2) further predict that the p.Arg366Cys variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Andresen BS 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. Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996 Apr;5(4):461-72. 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. Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. 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. Spiekerkoetter U et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr. 2010 Oct;157(4):668-73.
Counsyl RCV000675110 SCV000800658 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-01-30 criteria provided, single submitter clinical testing
Invitae RCV000675110 SCV000832501 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 366 of the ACADVL protein (p.Arg366Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs771874163, ExAC 0.02%). This variant has been reported in combination with two other ACADVL variants in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, Invitae) and in affected individuals in whom no second allele was reported (PMID: 21932095, 9973285). In one of these individuals the variant was observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with this condition. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Arg326Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 203579). 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. A different missense substitution at this codon (p.Arg366His) has been determined to be pathogenic (PMID: 24263034, 16488171, 20060901, 27246109) and is also known as p.Arg326His in the literature. This suggests that the arginine residue is critical for ACADVL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000675110 SCV001364914 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1096C>T (NP_000009.1:p.Arg366Cys) [GRCH38: NC_000017.11:g.7223151C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Natera, Inc. RCV000675110 SCV001455138 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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