ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.476A>G (p.Gln159Arg)

gnomAD frequency: 0.00001  dbSNP: rs746688190
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV001200731 SCV002576774 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2022-09-20 reviewed by expert panel curation The c.476A>G (p.Gln159Arg) variant in ACADVL is a missense in exon 6. This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID: 9973285). The highest population minor allele frequency in gnomAD is 0.00003 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.90, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). There is however insufficient experimental or case data identified in the literature for this variant and is therefore classified as a VUS. (ACADVL-specific ACMG/AMP criteria applied: PP4; PM2_supporting; PP3).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001200731 SCV001364889 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.476A>G (NP_000009.1:p.Gln159Arg) [GRCH38: NC_000017.11:g.7221057A>G] 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 RCV001200731 SCV003443733 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2022-03-14 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 159 of the ACADVL protein (p.Gln159Arg). This variant is present in population databases (rs746688190, gnomAD 0.003%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 25456746). This variant is also known as Q119R. ClinVar contains an entry for this variant (Variation ID: 932787). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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