Submissions for variant NM_000018.4(ACADVL):c.1217A>C (p.Gln406Pro)

gnomAD frequency: 0.00001  dbSNP: rs1384021857

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685865	SCV000813365	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with proline at codon 406 of the ACADVL protein (p.Gln406Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. 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. 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: 566129). This missense change has been observed in individual(s) with clinical features of VLCAD deficiency (PMID: 30194637). This variant is not present in population databases (ExAC no frequency).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000685865	SCV001365206	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1217A>C (NP_000009.1:p.Gln406Pro) [GRCH38: NC_000017.11:g.7223678A>C] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000685865	SCV003934438	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-05-19	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1217A>C (p.Gln406Pro) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). c.1217A>C has been reported in the literature in an individual with clinical features of Very Long Chain Acyl-CoA Dehydrogenase Deficiency, however the individual was reported as heterozygous (example: Hesse_2018). This report does not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. D'Annibale_2022 has demonstrated this variant leads to near absent activity in vitro and authors proposed c.1217A>C, (p.Gln406Pro) be reclassified from VUS to pathogenic/likely pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 35218577, 30194637). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.