ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.753-2A>C (rs398123092)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000180449 SCV000486708 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-07-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077923 SCV000232891 pathogenic not provided 2013-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000077923 SCV000616632 pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing The c.753-2 A>C splice site variant in the ACADVL gene has been previously reported in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al., 1999; Evans et al., 2016). The c.753-2 A>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant destroys the canonical splice acceptor site in intron 8, and is expected to cause abnormal gene splicing.
Invitae RCV000180449 SCV000654967 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-08-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the ACADVL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs398123092, ExAC 0.001%). This variant has been reported in combination with other ACADVL variants in several individuals affected with VLCAD deficiency (PMID: 10738914, 27246109, 17999356, 10077518). ClinVar contains an entry for this variant (Variation ID: 92290). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 24801231). For these reasons, this variant has been classified as Pathogenic.

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