rs1057520088
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3PM2_SupportingPP4PP3
This summary comes from the ClinGen Evidence Repository: The c.364A>G (p.Asn122Asp) variant in ACADVL is a missense in exon 6. This variant has been reported as a homozygote in the literature associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID:34480364). Fatty acid oxidation (FAO) flux assay performed on patient fibroblast homozygous for this variant demonstrated severe reduction of enzyme activity (PS3, PMID:20060901). In additon, protein production was deficient for this genotype shown by western blot (PMID:20060901). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.86, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: (PP4,PP3, PS3, PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603209/MONDO:0008723/021
Frequency
Consequence
ENST00000356839.10 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.364A>G | p.Asn122Asp | missense_variant | 6/20 | ENST00000356839.10 | NP_000009.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.364A>G | p.Asn122Asp | missense_variant | 6/20 | 1 | NM_000018.4 | ENSP00000349297 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461812Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727192
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 09, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 376917). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 20060901). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 122 of the ACADVL protein (p.Asn122Asp). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2023 | Variant summary: ACADVL c.364A>G (p.Asn122Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251418 control chromosomes. c.364A>G has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Gobin-Limballe_2007, Merritt_2014, Sharma_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in considerably decreased VLCAD activity (Gobin-Limballe_2007, Tenopoulou_2015). The following publications have been ascertained in the context of this evaluation (PMID: 17999356, 24503138, 34480364, 25737446). Six submitters including an expert panel (ClinGen ACADVL Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 21, 2021 | The ACADVL c.364A>G; p.Asn122Asp variant (rs1057520088), has been reported in an individual with VLCAD deficiency who was homozygous for the variant, and cultured fibroblasts from this individual showed extremely low residual VLCAD protein levels and severe FAO-deficiency (Gobin-Limballe 2010, Gobin-Limballe 2007). Additionally, our laboratory has previously identified this variant in an affected individual who was apparently homozygous for the variant by Sanger sequencing. This variant is also reported in ClinVar (Variation ID: 376917). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 122 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL 0.856). Based on available information, this variant is considered to be pathogenic. References: Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007 Dec;81(6):1133-43. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 09, 2021 | - - |
Pathogenic, 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.364A>G (NP_000009.1:p.Asn122Asp) [GRCH38: NC_000017.11:g.7220945A>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | May 06, 2022 | The c.364A>G (p.Asn122Asp) variant in ACADVL is a missense in exon 6. This variant has been reported as a homozygote in the literature associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID: 34480364). Fatty acid oxidation (FAO) flux assay performed on patient fibroblast homozygous for this variant demonstrated severe reduction of enzyme activity (PS3, PMID: 20060901). In additon, protein production was deficient for this genotype shown by western blot (PMID: 20060901). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.86, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: (PP4,PP3, PS3, PM2_Supporting). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34436479, 20060901, 34480364, 33610471) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at