Submissions for variant NM_000018.4(ACADVL):c.339C>A (p.Phe113Leu)

dbSNP: rs750653177

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000541584	SCV002769761	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-13	reviewed by expert panel	curation	The c.339C>A variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 113 (p.(Phe113Leu)). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID: 21932095; c.848T>C, p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). This individual had NBS C14:1 levels (1.10 uM) above the threshold of ≥ 1.0 μM as specified by the ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID: 21932095) (PP4_Moderate). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP. In summary, this variant meets the criteria to be classified as UNCERTAIN SIGNIFICANCE 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 (ClinGen ACADVL VCEP specifications version #1.0; approved 2022-12-13)
Invitae	RCV000541584	SCV000654951	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-12-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with very longchain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 30194637). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 474895). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 113 of the ACADVL protein (p.Phe113Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000541584	SCV001364884	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.339C>A (NP_000009.1:p.Phe113Leu) [GRCH38: NC_000017.11:g.7220827C>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3