Submissions for variant NM_000018.4(ACADVL):c.1064T>C (p.Ile355Thr)

gnomAD frequency: 0.00001  dbSNP: rs1351976589

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000813585	SCV000953951	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 355 of the ACADVL protein (p.Ile355Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with VLCAD deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 657040). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADVL protein function. For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000813585	SCV001365075	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1064T>C (NP_000009.1:p.Ile355Thr) [GRCH38: NC_000017.11:g.7222852T>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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226399	SCV003922433	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1064T>C (p.Ile355Thr) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250672 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1064T>C has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Miller_2015). The report does 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. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.