ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.364A>G (p.Asn122Asp) (rs1057520088)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000432463 SCV000510871 pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Invitae RCV000690847 SCV000818576 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-06-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 122 of the ACADVL protein (p.Asn122Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another ACADVL variant in individuals affected with very long chain acyl-CoA dehydrogenase deficiency (PMID: 20060901). ClinVar contains an entry for this variant (Variation ID: 376917). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000690847 SCV000883341 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-09-26 criteria provided, single submitter clinical testing The ACADVL c.364A>G; p.Asn122Asp variant (rs1057520088) has been reported in an individual with VLCAD deficiency who was homozygous for the variant, and cultured fibroblasts from this individual showed extremely low residual VLCAD protein levels and severe FAO-deficiency (Gobin-Limballe 2010, Gobin-Limballe 2007). Additionally, our laboratory has previously identified this variant in an affected individual who was apparent homozygous for the variant. This variant is reported as pathogenic in ClinVar (Variation ID: 376917), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database). Based on available information, this variant is considered pathogenic. REFERENCES Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007 Dec;81(6):1133-43.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000690847 SCV001364887 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.364A>G (NP_000009.1:p.Asn122Asp) [GRCH38: NC_000017.11:g.7220945A>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

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