ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1406G>A (p.Arg469Gln)

gnomAD frequency: 0.00001  dbSNP: rs398123083
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000169627 SCV002769758 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-10-12 reviewed by expert panel curation The c.1406G>A variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 469 (p.Arg469Trp). This variant has been detected in 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency; of the 3 homozygous individuals, 2 were monozygotic twins; in one heterozygous individual, a second distinct pathogenic variant in ACADVL was not observed. (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). At least one patient with this variant displayed ACADVL enzyme activity of <20% of normal which is highly specific for VLCADD (PP4_Moderate, PMID: 25834949). Another missense variant c.1405C>T (p.Arg469Trp) [VCV000021017.19, PMIDs: 9973285, 17374501, 17999356] in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285) (PM1). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, 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: PM3, PP4_Moderate, PM5, PM1, PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-16-2022).
Counsyl RCV000169627 SCV000221156 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2015-02-25 criteria provided, single submitter literature only
Eurofins Ntd Llc (ga) RCV000790745 SCV000225985 pathogenic not provided 2012-08-06 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000169627 SCV001364931 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1406G>A (NP_000009.1:p.Arg469Gln) [GRCH38: NC_000017.11:g.7224041G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Invitae RCV000169627 SCV001413446 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 469 of the ACADVL protein (p.Arg469Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 25834949). This variant is also known as R429Q. ClinVar contains an entry for this variant (Variation ID: 92276). 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%. This variant disrupts the p.Arg469 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9973285, 17374501, 17999356, 27246109). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169627 SCV004211910 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-03-15 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169627 SCV002088796 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-12-31 no assertion criteria provided clinical testing

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