ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.342+1G>C

dbSNP: rs780020193
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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 RCV000556138 SCV002538676 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-02-07 reviewed by expert panel curation The c.342+1G>C variant in ACADVL occurs within the canonical splice donor site of intron 5. It is predicted to cause skipping of biologically-relevant-exon 5, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Moderate). This variant is reported in at least one patient with severe hypoglycemia and postmortem C14:1 measurement of 1.35uM (PP4, PMID: 20107901). In addition, this patient carried the p.Val283Ala mutation. In summary, this variant meets the criteria to be classified as 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, PP4_Moderate).
Invitae RCV000556138 SCV000654952 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-11-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 20107901). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 474896). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000556138 SCV001364885 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.342+1G>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7220831G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20107901. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3

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