ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1077+2T>C (rs1057516370)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411047 SCV000485541 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-01-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090638 SCV001246299 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411047 SCV001338229 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-02-29 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1077+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249894 control chromosomes. c.1077+2T>C has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency with a characteristic acyl-carnitine profile (example, Andersen_1999, Scalais_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Scalais_2015). This relatively high VLCAD activity in lymphocytes was attributed to oral riboflavin supplementation at the time of analysis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as 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 RCV000411047 SCV001364913 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1077+2T>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222867T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 25338548. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Invitae RCV000411047 SCV001402471 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-08-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the ACADVL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 25338548, 30194637, 9973285). ClinVar contains an entry for this variant (Variation ID: 370279). 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, 11590124). For these reasons, this variant has been classified as Pathogenic.

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