ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1532+2T>C

dbSNP: rs111851815
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000411534 SCV004176828 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-12-14 reviewed by expert panel curation The c.1532+2T>C variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 15. It is predicted to cause skipping of biologically-relevant-exon 15/20, 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). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1 is 0.00005440 in the East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (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. (ACADVL VCEP specifications version 1; approved November 8, 2021)
Counsyl RCV000411534 SCV000486171 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-04-13 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000411534 SCV001364981 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1532+2T>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224245T>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
Invitae RCV000411534 SCV002309910 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-08-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs111851815, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 370770). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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