rs200788251
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_SupportingPP4_ModeratePM3PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID:14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID:14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337873/MONDO:0008723/021
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.865G>A | p.Gly289Arg | missense_variant | 9/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.865G>A | p.Gly289Arg | missense_variant | 9/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251232Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135840
GnomAD4 exome AF: 0.000201 AC: 294AN: 1461744Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 139AN XY: 727176
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74470
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 02, 2021 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Jun 27, 2023 | The c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID: 14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID: 14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 12, 2023 | Variant summary: ACADVL c.865G>A (p.Gly289Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251232 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00011 vs 0.0029), allowing no conclusion about variant significance. c.865G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, PMID: 14517516, 27209629, 31031081, 30194637). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 23480858). The most pronounced variant effect results in 15% of normal VLCAD activity in-vitro. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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.865G>A (NP_000009.1:p.Gly289Arg) [GRCH38: NC_000017.11:g.7222289G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516; 27209629 . This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 02, 2023 | PM1, PM2, PM3, PP2, PP3, PP5 - The variant has been reported in ClinVar by other laboratories (Variation ID 370981). Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It was detected in trans with another pathogenic variant. It has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (PMID: 31031081, 30194637). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 289 of the ACADVL protein (p.Gly289Arg). This variant is present in population databases (rs200788251, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 14517516, 23480858, 27209629, 27246109). ClinVar contains an entry for this variant (Variation ID: 370981). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 23480858). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 22, 2018 | Across a selection of the available literature, the ACADVL c.865G>A (p.Gly289Arg) variant has been reported in a compound heterozygous state in at least six individuals identified as having VLCAD deficiency through newborn screening (Spiekerkoetter et al. 2003; Schiff et al. 2013; Waisbren et al. 2013; Pena et al. 2016; Evans et al. 2016). Several of these individuals were described as asymptomatic, however, speech/language and motor delays, autistic spectrum behavior and relative weakness in the fine motor area were reported in two individuals after at least two years of follow-up (Waisbren et al. 2013). Analysis of 693 unrelated individuals with a positive newborn screening result for VLCAD deficiency, identified the p.Gly289Arg variant on six alleles from affected individuals (Miller et al. (2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Fibroblasts from one individual who was compound heterozygous for the p.Gly289Arg variant, exhibited no detectable enzyme activity and absent protein expression based on Western blot analysis. In vitro expression analyses in E. coli showed that the p.Gly289Arg variant displayed 15% of wildtype activity and reduced protein expression (Schiff et al. 2013). Based on the collective evidence, the p.Gly289Arg variant is classified as pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2019 | The ACADVL c.865G>A; p.Gly289Arg variant (rs200788251), also known as p.Gly249Arg, is reported in the literature in the compound heterozygous state in individuals affected with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Evans 2016, Pena 2016, Schiff 2013, Spiekerkoetter 2003). This variant is also reported in ClinVar (Variation ID: 370981). It is found in the general population with an overall allele frequency of 0.01% (32/282608 alleles) in the Genome Aggregation Database. The glycine at codon 289 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, in vitro functional analyses demonstrate a significant reduction in protein activity compared to wildtype (Schiff 2013). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. 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. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 109(1):21-7. Spiekerkoetter U et al. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2003 143(3):335-42. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | Published functional studies demonstrate a damaging effect. Expression of G289R in E. coli found that it is associated with approximately 15% residual enzyme activity (Schiff et al., 2013).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23798014, 27209629, 25087612, 25242572, 23480858, 14517516, 20547398, 30194637, 21228398, 31031081, 31980526, 33658040, 32778825, 31589614) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at