ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln)

dbSNP: rs118204015
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000001695 SCV002769765 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-12-15 reviewed by expert panel curation The NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 382. The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_ Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who was compound heterozygous for the variant and a pathogenic variant confirmed in trans by molecular subcloning (PM3, PMID: 8554073). The reported patient with this variant displayed reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID: 7769092). VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PS3_Supporting, PMID: 8554073). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.95, 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 ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PM3, PP3, PM2_Supporting, PS3_Supporting, PP4_Moderate).
Invitae RCV000001695 SCV001585423 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-05-27 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 382 of the ACADVL protein (p.Lys382Gln). This variant is present in population databases (rs118204015, gnomAD 0.006%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADVL function (PMID: 8554073). 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. ClinVar contains an entry for this variant (Variation ID: 1628). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8554073, 20060901, 29552494, 31497477).
OMIM RCV000001695 SCV000021851 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1996-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000001695 SCV002088781 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-08-04 no assertion criteria provided clinical testing

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