Submissions for variant NM_000018.4(ACADVL):c.476A>G (p.Gln159Arg)

gnomAD frequency: 0.00001  dbSNP: rs746688190

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001200731	SCV002576774	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-20	reviewed by expert panel	curation	The c.476A>G (p.Gln159Arg) variant in ACADVL is a missense in exon 6. This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4; PMID: 9973285). The highest population minor allele frequency in gnomAD is 0.00003 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.90, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). There is however insufficient experimental or case data identified in the literature for this variant and is therefore classified as a VUS. (ACADVL-specific ACMG/AMP criteria applied: PP4; PM2_supporting; PP3).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200731	SCV001364889	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.476A>G (NP_000009.1:p.Gln159Arg) [GRCH38: NC_000017.11:g.7221057A>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200731	SCV003443733	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-03-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 159 of the ACADVL protein (p.Gln159Arg). This variant is present in population databases (rs746688190, gnomAD 0.003%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 25456746). This variant is also known as Q119R. ClinVar contains an entry for this variant (Variation ID: 932787). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001200731	SCV005091017	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-02	criteria provided, single submitter	clinical testing	PM1, PM2, PM3, PP2, PP3, PP5 - The variant has been reported in ClinVar by other laboratories (Variation ID 932787). Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It was detected in trans with another pathogenic variant.