Submissions for variant NM_000018.4(ACADVL):c.760G>A (p.Gly254Ser)

gnomAD frequency: 0.00005  dbSNP: rs765423779

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200691	SCV001365045	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.760G>A (NP_000009.1:p.Gly254Ser) [GRCH38: NC_000017.11:g.7222184G>A] 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: PM1
Invitae	RCV001200691	SCV001533779	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 254 of the ACADVL protein (p.Gly254Ser). This variant is present in population databases (rs765423779, gnomAD 0.03%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase 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: 932752). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly254 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28755339; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230646	SCV003929135	uncertain significance	not specified	2023-04-25	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.760G>A (p.Gly254Ser) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.760G>A has not been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001200691	SCV004563267	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-08-22	criteria provided, single submitter	clinical testing	The ACADVL c.760G>A; p.Gly254Ser variant (rs765423779) is reported in the homozygous state in an individual with very long chain acyl-coA dehydrogenase (VLCAD) deficiency. Functional analyses showed that lymphocytes derived from this individual showed reduced enzymatic activity (Merinero 2018). This variant is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 254 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL=0.866). Based on available information, this variant is considered to be likely pathogenic. References: Merinero B et al. Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. JIMD Rep. 2018.
Natera, Inc.	RCV001200691	SCV002088764	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-05-15	no assertion criteria provided	clinical testing