ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1679-6G>A (rs113994171)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000031857 SCV000221101 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2015-01-29 criteria provided, single submitter literature only
GeneDx RCV000185730 SCV000238656 pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing The c.1679-6 G>A variant in the ACADVL gene has been reported previously in association with verylong chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al., 1996; Cox et al., 1998).The c.1679-6 G>A variant resulted in no detectable mRNA by Northern blot analysis and barelydetectable mRNA by RT-PCR (Andresen et al., 1996). The c.1679-6 G>A variant is not observed at asignificant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al.,2015; Exome Variant Server). In summary, we interpret c.1679-6 G>A as pathogenic.
Invitae RCV000031857 SCV000654941 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-16 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the ACADVL gene. It does not directly change the encoded amino acid sequence of the ACADVL protein. This variant is present in population databases (rs113994171, ExAC 0.1%). This variant has been reported as homozygous or in combination with other pathogenic ACADVL variants in individuals affected with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9709714, 23480858, 9973285). ClinVar contains an entry for this variant (Variation ID: 21019). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000031857 SCV000894150 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000031857 SCV001337879 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-01-06 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1679-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. One predicts the variant abolishes a 3' acceptor site and another that it weakens a 3' acceptor site. Experimental evidence also suggests that this variant affects normal mRNA splicing (Cox_1998, Andresen_1999). The variant allele was found at a frequency of 2.2e-05 in 92036 control chromosomes (gnomAD). c.1679-6G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Cox_1998, Andresen_1999, Schiff_2013). VLCAD enzymatic activity was not detected from patient's fibroblasts samples who harbored this variant and another pathogenic variant (Schiff_2013).These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000031857 SCV001364938 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1679-6G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224636G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9709714. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000031857 SCV001472009 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-04-02 criteria provided, single submitter clinical testing The ACADVL c.1679-6G>A variant (rs113994171) is reported in the literature in multiple individuals affected with VLCAD deficiency, both in homozygous and compound heterozygous individuals (Andresen 1996, Andresen 1999, Cox 1998, Schiff 2013). This variant is found on only two chromosomes in the Genome Aggregation Database (2/92036 alleles), indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Consistent with these predictions, analyses of mRNAs from individuals with this variant indicate decreased mRNA levels and insertion of four nucleotides due to usage of the cryptic splice acceptor (Andresen 1996, Cox 1998). 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. Cox GF et al. Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 1998 Aug;133(2):247-53. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7.
Natera, Inc. RCV000031857 SCV001459264 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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