ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1605+2T>C

dbSNP: rs1597537351
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000812878 SCV003936872 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-09-05 reviewed by expert panel curation The c.1605+2T>C (p.?) variant in ACADVL occurs within the canonical splice donor site (+2) of intron 16. It is predicted to cause skipping of biologically-relevant-exon 16/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 09-05-2022).
Labcorp Genetics (formerly Invitae), Labcorp RCV000812878 SCV000953208 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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). 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. Disruption of this splice site has been observed to be in combination with another ACADVL variant in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 24801231). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 16 of the ACADVL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000812878 SCV001364983 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1605+2T>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224395T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

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