ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.779C>T (p.Thr260Met)

gnomAD frequency: 0.00005
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020080 SCV000220919 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-11-25 criteria provided, single submitter literature only
GeneDx RCV000429481 SCV000511943 pathogenic not provided 2020-06-17 criteria provided, single submitter clinical testing Published functional studies found T260M is associated with significantly reduced enzyme activity (Andresen et al., 1999; Goetzman et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20480395, 17374501, 25087612, 20060901, 9973285, 8845838, 21932095, 27943070, 30194637, 16950999, 20301763, 10077518, 19327992, 31589614)
Invitae RCV000020080 SCV000654968 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 260 of the ACADVL protein (p.Thr260Met). This variant is present in population databases (rs113994168, gnomAD 0.003%). This missense change has been observed in individual(s) with very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 19327992, 20060901, 21932095). ClinVar contains an entry for this variant (Variation ID: 21024). 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. Experimental studies have shown that this missense change affects ACADVL function (PMID: 9973285, 17374501, 19327992). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020080 SCV000916407 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-07-02 criteria provided, single submitter clinical testing Variant summary: ACADVL c.779C>T (p.Thr260Met) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246264 control chromosomes (gnomAD). c.779C>T has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency as both a homozygous and compound heterozygous allele (Liebig_2006, Laforet_2009). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing a significant decrease (<10% of normal) in VLCAD activity in patient fibroblasts (Laforet_2009). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000020080 SCV001156588 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-02-23 criteria provided, single submitter clinical testing The ACADVL c.779C>T; p.Thr260Met variant (rs113994168), also known as Thr220Met, has been reported in multiple individuals diagnosed with very long chain acyl-CoA dehydrogenase deficiency, often found in-trans with another pathogenic variant (Andresen 1996, Andresen 1999, Gobin-Limballe 2010, Laforet 2009, Mathur 1999). Additionally, functional characterization of the variant protein in patient fibroblasts demonstrate significantly decreased enzymatic activity (Andresen 1996, Andresen 1999, Hoffman 2012, Laforet 2009). This variant is reported in ClinVar (Variation ID: 21024) and observed in the general population at a low overall frequency of 0.002% (5/246264 alleles) in the Genome Aggregation Database. The threonine at residue 260 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Based on available information, this variant is considered pathogenic. References: Andresen B 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; 5(4):461-72. PMID: 8845838. 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. PMID: 9973285. 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. PMID: 20060901. 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. PMID: 21932095. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009; 19(5):324-9. PMID: 19327992. Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10):1337-43. PMID: 10077518.
Baylor Genetics RCV000020080 SCV001163798 pathogenic Very long chain acyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000020080 SCV001364903 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.779C>T (NP_000009.1:p.Thr260Met) [GRCH38: NC_000017.11:g.7222203C>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
Institute of Human Genetics, University Hospital Muenster RCV001807005 SCV002054128 pathogenic Very long chain fatty acid accumulation 2021-12-04 criteria provided, single submitter clinical testing ACMG categories: PS5,PM1,PM2,PM3,PP3,PP4,PP5,BP1
Natera, Inc. RCV000020080 SCV001455129 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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