Submissions for variant NM_000018.4(ACADVL):c.605T>C (p.Leu202Pro)

gnomAD frequency: 0.00001  dbSNP: rs398123090

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	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 (ga)	RCV000723640	SCV000109750	uncertain significance	not provided	2013-05-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723640	SCV000602360	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	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
Invitae	RCV001200734	SCV001487425	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-05-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 92288). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 30194637). This variant is present in population databases (rs398123090, gnomAD no frequency). 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).
GeneDx	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)
CeGaT Center for Human Genetics Tuebingen	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