ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1077+1G>T (rs140989450)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412397 SCV000485817 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-02-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000412397 SCV000916404 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-07-10 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1077+1G>T 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: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249894 control chromosomes. c.1077+1G>T has been reported in the literature in at least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency with residual enzyme activity of 36%. A second mutation was not identifed in this patient (Hoffmann_2012). The variant has also been reported in a patient with familial dilated cardiomyopathy, however co-occurrence with a pathogenic mutation in TTN (c.49458G>A, p.W16486X) was reported in this individual (Minoche_2019). These data do not allow any conclusion about variant significance. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000412397 SCV000954513 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-19 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). This variant has been observed as heterozygous in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095). ClinVar contains an entry for this variant (Variation ID: 370482). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000412397 SCV001364911 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1077+1G>T (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222866G>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

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