ClinVar Miner

Submissions for variant NM_000018.2(ACADVL):c.343delG (p.Glu115Lysfs) (rs387906249)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077915 SCV000231447 pathogenic not provided 2013-03-18 criteria provided, single submitter clinical testing
GeneDx RCV000077915 SCV000576837 pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The c.343delG variant in the ACADVL gene has been reported previously in association with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Strauss et al., 1995; Ndukwe et al., 2013; Evans et al., 2016). The c.343delG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.343delG variant causes a frameshift starting with codon Glutamic Acid 115, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Glu115LysfsX2. The c.343delG variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.343delG as pathogenic.
Invitae RCV000001691 SCV000773901 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu115Lysfs*2) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs387906250, ExAC 0.002%). This variant has been reported in combination with another ACADVL variant in two individuals affected with very long chain acyl-CoA dehydrogenase (PMID: 27246109, 23867825). ClinVar contains an entry for this variant (Variation ID: 1624). Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000001691 SCV001364886 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.343delG (NP_000009.1:p.Glu115LysfsTer2) [GRCH38: NC_000017.11:g.7220924delG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 7479827. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001691 SCV001372383 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-06-20 criteria provided, single submitter clinical testing Variant summary: ACADVL c.343delG (p.Glu115LysfsX2 also referred to as c.343-1delG) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant also deletes a conserved exonic nucleotide located adjacent to intron 5 splice acceptor site of the ACADVL gene: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 277170 control chromosomes (gnomAD). c.343delG has been reported in the literature in multiple compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency ( example, Strauss 1995, Mathur 1999, Evans 2016, Gillingham 2017, Ndukwe Erlingsson 2013, Olpin 2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function (example, Hesse 2018, Mathur 1999, Strauss 1995). The most pronounced variant effect results in <10% of normal activity in cell lines bearing this variant as a compound heterozygous genotype, while the variant results in 32% of normal activity in heterozygous patient fibroblasts. Three 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 pathogenic (n=2)/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001691 SCV000021847 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1995-11-07 no assertion criteria provided literature only
Counsyl RCV000001691 SCV000220752 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2015-10-09 no assertion criteria provided clinical testing

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