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

dbSNP: rs796051914

Total submissions: 4

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	2021-10-10	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 individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 25456746, 26385305). ClinVar contains an entry for this variant (Variation ID: 203590). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant 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	2023-02-22	criteria provided, single submitter	clinical testing	The ACADVL c.889_891delGAG; p.Glu297del variant (rs796051914), also known as Glu257del, deletes three nucleotides and results 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, ARUP Laboratories has identified this variant in several heterozygous carriers and in a symptomatic 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). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be 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. PMID: 25456746. 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. PMID: 26385305. 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. PMID: 27209629.