Submissions for variant NM_000018.4(ACADVL):c.1072A>G (p.Lys358Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV002952436	SCV003936868	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-13	reviewed by expert panel	curation	The c.1072A>G (p.Lys358Glu) variant in ACADVL is a missense in exon 10. This variant has been reported twice as compound heterozygote with pathogenic variants (p.V283A & p.His181Profs72) in patients with ACADVL deficiency (PMID: 25834949, 21932095, PM3). Both patients with this variant displayed reduced enzyme activity, which is highly specific for ACADVL deficiency (PP4_moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.69, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limiting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP4_moderate, PM3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002952436	SCV003267975	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 358 of the ACADVL protein (p.Lys358Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 25834949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.K318E. ClinVar contains an entry for this variant (Variation ID: 2058739). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.