ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.896A>T (p.Lys299Met)

gnomAD frequency: 0.00001  dbSNP: rs771247610
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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 RCV001200782 SCV003936878 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-06-13 reviewed by expert panel curation The c.896A>T (p.Lys299Met) variant in ACADVL has been reported in the literature in patients with VLCAD deficiency and elevated acylcarnitine (PP4_moderate; PMID: 16982043, 35281659). The variant has also been detected in compound heterozygote with pathogenic variant p.Val283Ala (PM3; PMID: 35281659). Three missense variants (p.Lys299Asn, p.Lys299Arg, p.Lys299Glu; PMIDs: 9973285, 31737040, 33150772) in the same codon have also been reported for VLCAD deficiency. This variant is absent from gnomAD population database v2.1.1(PM2_Supporting) and the computational predictor REVEL gives a score of 0.963, 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 (PP4_moderate, PM3, PM2_Supporting, PP3).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001200782 SCV001364910 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.896A>T (NP_000009.1:p.Lys299Met) [GRCH38: NC_000017.11:g.7222684A>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 16982043 . This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Invitae RCV001200782 SCV002243866 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-09-26 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 299 of the ACADVL protein (p.Lys299Met). This variant is present in population databases (rs771247610, gnomAD 0.003%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 16982043, 25652019, 30194637, 31794763). This variant is also known as p.K259M. ClinVar contains an entry for this variant (Variation ID: 932829). 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001200782 SCV004216157 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-01-04 criteria provided, single submitter clinical testing

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