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

gnomAD frequency: 0.00005  dbSNP: rs765423779

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200691	SCV001533779	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2025-01-21	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 (internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACADVL protein function with a negative predictive value of 80%. 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; internal data). 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	2024-11-19	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. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.760G>A has been reported in the literature in at least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Labcorp (formerly Invitae) Internal case). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 932752). 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.
Fulgent Genetics, Fulgent Genetics	RCV001200691	SCV005650579	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-06-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001200691	SCV002088764	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-05-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754700	SCV005354288	uncertain significance	ACADVL-related disorder	2024-04-01	no assertion criteria provided	clinical testing	The ACADVL c.760G>A variant is predicted to result in the amino acid substitution p.Gly254Ser. This variant was found in an infant with a positive newborn screening for VLCAD deficiency (Miller et al. 2015. PubMed ID: 26385305). An alternate nucleotide change affecting the same amino acid (p.Gly254Asp), has been reported in the homozygous state in two infants with positive newborn screenings for VLCAD deficiency (Merinero et al. 2018. PubMed ID: 28755359; Martín-Rivada et al. 2022. PubMed ID: 35281663). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.