ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1182+3G>T

gnomAD frequency: 0.00001  dbSNP: rs376281637
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001200753 SCV001365084 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1182+3G>T (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7223240G>T] 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: BP4
GeneDx RCV001551792 SCV001772372 uncertain significance not provided 2021-02-03 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 23480858, 27209629)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797826 SCV002041566 uncertain significance not specified 2021-11-07 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1182+3G>T 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251454 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1182+3G>T has been reported in the literature in one asymptomatic newborn within a setting of cohort referral because of a suspicion of VLCADD but some uncertainty in diagnosis (example, Schiff_2013 with overlapping reporting by Pena_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001200753 SCV003522467 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2022-04-03 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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376281637, gnomAD 0.003%). This variant has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 23480858; Invitae). ClinVar contains an entry for this variant (Variation ID: 932804). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Revvity Omics, Revvity Omics RCV001200753 SCV003822468 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2022-05-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV001200753 SCV004212726 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-08-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV001200753 SCV002088785 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2021-03-05 no assertion criteria provided clinical testing

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