Submissions for variant NM_000018.4(ACADVL):c.1024T>C (p.Phe342Leu)

gnomAD frequency: 0.00002  dbSNP: rs1356652354

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727590	SCV000854837	uncertain significance	not provided	2017-11-21	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200831	SCV001365065	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1024T>C (NP_000009.1:p.Phe342Leu) [GRCH38: NC_000017.11:g.7222812T>C] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant dose not meet any evidence codes reported in the ACMG guidelines.
Invitae	RCV001200831	SCV002205206	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-10	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 592247). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 24503138; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 342 of the ACADVL protein (p.Phe342Leu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489845	SCV004241018	uncertain significance	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1024T>C (p.Phe342Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1024T>C has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g., Merritt_2014, Miller_2015, Adhikari_2020). However, these reports do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 24503138, 26385305). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.