rs138834083
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_000018.4(ACADVL):c.1273G>A(p.Ala425Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A425V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1273G>A | p.Ala425Thr | missense_variant | 13/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1273G>A | p.Ala425Thr | missense_variant | 13/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251466Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461854Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727228
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74364
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 01, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | 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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 19, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 24, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2022 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 07, 2021 | PP1, PP4_moderate, PM2, PS4_moderate - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at