ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1368dup (p.Ile457fs)

gnomAD frequency: 0.00001  dbSNP: rs1175359422
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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 RCV000818697 SCV002769784 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-12-14 reviewed by expert panel curation The c.1368dup (p.Ile457fs) also known as (p.Ile457HisfsTer6) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon14/20 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 for to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001549 in the European (non-Finnish) 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 VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (VCEP specifications version1; approved November 8, 2021)
Invitae RCV000818697 SCV000959323 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile457Hisfs*6) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal 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: 661308). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000818697 SCV001364980 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1368dupC (NP_000009.1:p.Ile457HisfsTer6) [GRCH38: NC_000017.11:g.7224003dup] 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
Baylor Genetics RCV000818697 SCV004211798 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-04-19 criteria provided, single submitter clinical testing

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