Submissions for variant NM_000018.4(ACADVL):c.533T>C (p.Leu178Pro)

dbSNP: rs1131691808

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493429	SCV000582888	likely pathogenic	not provided	2016-06-21	criteria provided, single submitter	clinical testing	The L178P variant has been reported previously, using alternate nomenclature, in an individual who had a positive newborn screening result for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency in whom a second variant was not identified in the ACADVL gene and in whom residual VLCAD enzyme activity was 33% (Hoffmann et al. 2012). The L178P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L178P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and L178 is located in the substrate binding cavity of the VLCAD protein (Hoffmann et al. 2012). In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200737	SCV001365030	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.533T>C (NP_000009.1:p.Leu178Pro) [GRCH38: NC_000017.11:g.7221593T>C] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM1, PM3, PP3, PP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001200737	SCV001473227	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-09-18	criteria provided, single submitter	clinical testing	The ACADVL c.533T>C; p.Leu178Pro variant (rs1131691808), also published as p.Leu138Pro, is reported in the literature in an individual with a positive newborn screen for VLCAD deficiency and a residual enzyme activity measured at 33% of normal (Hoffman 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 178 is moderately conserved, it occurs in the substrate binding cavity (Hoffman 2012), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200737	SCV002143288	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the ACADVL protein (p.Leu178Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency although a second variant was not observed (PMID: 21932095). ClinVar contains an entry for this variant (Variation ID: 430156). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. 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.
Ambry Genetics	RCV002524042	SCV003552458	uncertain significance	Inborn genetic diseases	2021-01-15	criteria provided, single submitter	clinical testing	The c.533T>C (p.L178P) alteration is located in exon 7 (coding exon 7) of the ACADVL gene. This alteration results from a T to C substitution at nucleotide position 533, causing the leucine (L) at amino acid position 178 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.