ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs138834083
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Total submissions: 7
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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 likely pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing The A425T variant has been reported previously in patients with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, diagnosed after an abnormal newborn screening result, who also harbored a second variant in the ACADVL gene (Chien et al. 2013; Pena et al. 2016). A425T has also been 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). This variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The A425T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In summary, we interpret this variant as likely pathogenic.
Invitae RCV000652034 SCV000773895 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-12-09 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. 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

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