Submissions for variant NM_000018.4(ACADVL):c.1096C>T (p.Arg366Cys)

gnomAD frequency: 0.00003  dbSNP: rs771874163

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185719	SCV000238644	likely pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9973285, 8845838, 21932095, 26385305, 31980526)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000185719	SCV000281260	pathogenic	not provided	2014-05-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000675110	SCV000602375	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-11-15	criteria provided, single submitter	clinical testing	The ACADVL c.1096C>T; p.Arg366Cys variant (rs771874163) has been reported in individuals with VLCAD deficiency (Andresen 1996) or in abnormal newborn results (Hoffmann 2012, Spiekerkoetter 2010). Analysis of enzymatic activity indicates that the variant protein has reduced activity compared to wildtype, with individuals showing residual activity less than 50 percent in fibroblasts (Hoffmann 2012) or lymphocytes (Spiekerkoetter 2010). This variant is also reported in ClinVar (Variation ID: 203579). It is only found on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 366 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.955). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996; 5(4):461-72. PMID: 8845838. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2):269-77. PMID: 21932095. Spiekerkoetter U et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr. 2010; 157(4):668-73. PMID: 20547398.
Invitae	RCV000675110	SCV000832501	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 366 of the ACADVL protein (p.Arg366Cys). This variant is present in population databases (rs771874163, gnomAD 0.007%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, 9973285, 21932095; 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 also known as p.Arg326Cys. ClinVar contains an entry for this variant (Variation ID: 203579). 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.Arg366 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16488171, 20060901, 24263034, 27246109). 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000675110	SCV001364914	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1096C>T (NP_000009.1:p.Arg366Cys) [GRCH38: NC_000017.11:g.7223151C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000675110	SCV002014886	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1096C>T (p.Arg366Cys) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase 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 allele was found at a frequency of 2e-05 in 251484 control chromosomes (gnomAD). c.1096C>T has been reported in the literature in individuals that were clinically diagnosed or identified via newborn screening to be affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1996, Miller_2015, Maguolo_2020, Osawa_2022). These data indicate that the variant is likely to be associated with disease. Experimental evidence showed decreased enzyme activity in compound heterozygous individuals with the variant (e.g. Andresen_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8845838, 8739957, 32793418, 26385305, 35400565). A different variant affecting the same codon (c.1097G>A , p.Arg366His) has been classified pathogenic in ClinVar (CV ID 203580). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000675110	SCV002061661	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-10-21	criteria provided, single submitter	clinical testing	PS3, PM3, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000185719	SCV002520065	pathogenic	not provided	2021-06-28	criteria provided, single submitter	clinical testing	PS3, PM2, PM5, PP3, PP4
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000675110	SCV003919970	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-03-30	criteria provided, single submitter	clinical testing	ACADVL NM_000018.3 exon 11 p.Arg366Cys (c.1096C>T): This variant (also referred to as Arg326Cys) has been reported in the literature in the compound heterozygous state and in the heterozygous state with no second allele identified in several individuals affected with VLCAD deficiency (Andresen 1996 PMID:8845838, Andresen 1999 PMID:9973285, Hoffmann 2012 PMID:21932095). This variant is present in 0.006% (1/16256) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-7126470-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:203579). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, another variant at the same amino acid residue (Arg366His, also referred to as Arg362His) has been associated with disease, supporting the potential functional relevance of this codon. In summary, this variant is classified as pathogenic based on the data above.
Baylor Genetics	RCV000675110	SCV004215892	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000675110	SCV004847522	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-07-23	criteria provided, single submitter	clinical testing	The p.Arg366Cys variant (also described as p.Arg326Cys in the literature) in ACADVL has been previously reported in the compound heterozygous state in 1 individual with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) with at least 1 additional disease-causing variant (Andresen 1996 PMID 8845838). It has also been reported in the heterozygous state at least individual with VLCADD without a second ACADVL variant identified (Hoffman 2012 PMID 21932095). This variant has also been reported by other clinical laboratories in ClinVar and was identified in 0.002% of pan ethnic chromosomes in gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with a recessive carrier allele frequency. Functional studies using patient derived cell lines show reduced enzyme activity as well as reduced ACADVL protein levels (Andresen 1996 PMID 8845838, Andresen 1999 PMID 9973285, Hoffman 2012 PMID 21932095). Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, another variant involving this codon (p.Arg366His) has been identified in several individuals with VLCADD and has been classified as pathogenic by multiple clinical laboratories (Boneh 2006 PMID 16488171, Gobin-Llimballe 2020 PMID 20060901, Antunes 2013 PMID 24263034, Evans 2016 PMID 27246109, ClinVar Variation ID: 203580). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive VLCADD. ACMG/AMP criteria applied: PM3_Supporting, PM2, PS3_Supporting, PP3, PM5.
Counsyl	RCV000675110	SCV000800658	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2018-01-30	flagged submission	clinical testing
Natera, Inc.	RCV000675110	SCV001455138	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing