Submissions for variant NM_000018.4(ACADVL):c.1273G>A (p.Ala425Thr)

gnomAD frequency: 0.00009  dbSNP: rs138834083

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000418569	SCV000109731	likely pathogenic	not provided	2018-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000418569	SCV000511945	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Identified in multiple individuals with a positive newborn screening result for VLCAD deficiency in whom a second variant in the ACADVL gene was not identified (Miller et al. 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27209629, 26385305, 23700290, 20480395)
Invitae	RCV000652034	SCV000773895	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 425 of the ACADVL protein (p.Ala425Thr). This variant is present in population databases (rs138834083, gnomAD 0.07%). This missense change has been observed in individuals with very long chain acyl-CoA dehydrogenase deficiency (PMID: 23700290, 27209629; Invitae). ClinVar contains an entry for this variant (Variation ID: 92273). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000652034	SCV000800548	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-06-19	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000652034	SCV001365209	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1273G>A (NP_000009.1:p.Ala425Thr) [GRCH38: NC_000017.11:g.7223816G>A] 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	RCV000652034	SCV001472008	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-02-01	criteria provided, single submitter	clinical testing	The ACADVL c.1273G>A; p.Ala425Thr variant (rs138834083) is reported in the literature in the heterozygous or compound heterozygous state with a second pathogenic variant in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (Chien 2013, Miller 2015, Pena 2016). This variant is reported in ClinVar (Variation ID: 92273), and is found in the African population with an allele frequency of 0.064% (16/24,966 alleles) in the Genome Aggregation Database. The alanine at codon 425 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.722). Based on available information, this variant is considered to be likely pathogenic. References: Chien YH et al. Fatty Acid oxidation disorders in a chinese population in taiwan. JIMD Rep. 2013;11:165-72. PMID: 23700290. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000418569	SCV002520066	likely pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing	PP1, PP4_moderate, PM2, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114240	SCV003800793	uncertain significance	not specified	2023-01-25	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1273G>A (p.Ala425Thr) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251466 control chromosomes. c.1273G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, PMID: 23700290, 31794763, 26385305, 27209629). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=4; P/LP, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000652034	SCV004210833	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-09-24	criteria provided, single submitter	clinical testing