ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.889_891del (p.Glu297del) (rs796051914)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185737 SCV000238665 likely pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing The c.889_891delGAG variant has been reported in an individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency who was heterozygous for another variant in the ACADVL gene (Brown et al., 2014). The c.889_891delGAG variant causes the loss of a single Glutamic Acid residue at amino acid position 297, denoted p.Glu297del. The Glu297 amino acid is a highly conserved residue that is located in a functional region of the ACADVL protein. Other deletions of single amino acids (p.Glu130del, p.Lys299del) have been reported in association with VLCAD deficiency (Souri et al., 1996). Therefore we interpret c.889_891delGAG to be a likely pathogenic variant.
Invitae RCV001061118 SCV001225850 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-06-16 criteria provided, single submitter clinical testing This variant, c.889_891del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu297del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with VLCAD (PMID: 25456746) and in several individuals with abnormal newborn screening results suggestive of VLCAD (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 203590). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. 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 RCV001061118 SCV001365053 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.889_891delGAG (NP_000009.1:p.Glu297del) [GRCH38: NC_000017.11:g.7222677_7222679del] 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: PP3
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001061118 SCV001474560 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-09-17 criteria provided, single submitter clinical testing The ACADVL c.889_891delGAG; p.Glu297del variant (rs796051914), also known as Glu257del, deletes three nucleotides resulting in an in-frame deletion of a single glutamate residue. This variant has been reported in a patient with a confirmed diagnosis of VLCAD deficiency who was also heterozygous for another ACADVL variant (Brown 2014), and is reported as a recurrent variant in positive newborn screening for VLCAD deficiency (Miller 2015). Additionally, our lab has identified this variant in several heterozygous carriers, and in an individual who carried an additional pathogenic ACADVL variant. Furthermore, other single amino acid deletions (Glu130del, Glu277del, Lys299del) have been reported in association with VLCAD deficiency (Miller 2015, Pena 2016). The p.Glu297del variant is reported in ClinVar (Variation ID: 203590), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, this variant is considered pathogenic. REFERENCES Brown A et al. Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab. 2014 Dec;113(4):278-82. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81.

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