ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1183-7A>G

dbSNP: rs750441118
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000687039 SCV002576740 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2022-09-22 reviewed by expert panel curation The c.1183-7A>G variant in ACADVL occurs within splice acceptor site of intron 11. The results from two in silico splicing predictors (MaxEntScn and Human Splicing Finder) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 11 of 20 in ACADVL (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed C14:1-carnitine level at 15.5 micromolar, which is highly specific for VLCAD deficiency (PP4_Supporting, PMID: 31031081). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, and PP4_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000687039 SCV000814589 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2021-09-02 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the ACADVL gene. It does not directly change the encoded amino acid sequence of the ACADVL protein. This variant is present in population databases (rs750441118, ExAC 0.001%). This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 31031081). ClinVar contains an entry for this variant (Variation ID: 567061). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000687039 SCV001365085 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1183-7A>G (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7223637A>G] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117488 SCV003801076 uncertain significance not specified 2023-01-25 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1183-7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site, and three predict the variant creates a cryptic 3' acceptor site located 6 nucleotides upstream into intron 11. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1183-7A>G has been reported in the literature in at least one compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Rovelli_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000687039 SCV002088786 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2020-07-23 no assertion criteria provided clinical testing

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