Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001200734 | SCV004805222 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2024-03-26 | reviewed by expert panel | curation | The NM_000018.4 c.605T>C (p.Leu202Pro) in ACADVL is a missense variant predicted to cause substitution of leucine by proline at amino acid 202 (p. Leu202Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000004 in the general population, 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 apparently heterozygous fashion in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who also displayed reduced enzyme levels (20% and 26% of wildtype, respectively), which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 23480858, 30194637). At least one individual with this variant was identified by very long chain acyl-CoA dehydrogenase (VLCAD) clinical phenotype, who also carried a pathogenic variant c.848T>C in trans, displaying reduced enzyme levels (4% of wildtype) (PM3 score = 1.0, PM3, PMID: 30194637). The computational predictor REVEL gives a score of 0.953, 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, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). |
Eurofins Ntd Llc |
RCV000723640 | SCV000109750 | uncertain significance | not provided | 2013-05-21 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000723640 | SCV000602360 | uncertain significance | not provided | 2017-10-26 | criteria provided, single submitter | clinical testing | |
Wong Mito Lab, |
RCV001200734 | SCV001364895 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2019-11-01 | criteria provided, single submitter | clinical testing | The NM_000018.3:c.605T>C (NP_000009.1:p.Leu202Pro) [GRCH38: NC_000017.11:g.7221665T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 23480858. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 |
Labcorp Genetics |
RCV001200734 | SCV001487425 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2024-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 202 of the ACADVL protein (p.Leu202Pro). This variant is present in population databases (rs398123090, gnomAD no frequency). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 30194637). ClinVar contains an entry for this variant (Variation ID: 92288). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 80%. This variant disrupts the p.Leu202 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32793418; internal data). 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. |
Gene |
RCV000723640 | SCV001779462 | uncertain significance | not provided | 2020-03-12 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30194637, 23480858) |
Ce |
RCV000723640 | SCV002498232 | pathogenic | not provided | 2022-01-01 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001200734 | SCV004216980 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-05-27 | criteria provided, single submitter | clinical testing |