Submissions for variant NM_000018.4(ACADVL):c.553G>A (p.Gly185Ser)

gnomAD frequency: 0.00001  dbSNP: rs545215807

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000412436	SCV002769756	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-14	reviewed by expert panel	curation	The c.553G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by serine at amino acid 185 (p.Gly185Ser). This variant has been detected in at least 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and distinct pathogenic variants (PM3, PMIDs: 31620161, 17999356). Two patients with this variant displayed beta Oxidation Flux <20% of normal and at least one individual showed increased acylcarnitines, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMIDs: 17999356, 31620161, 22841441). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PP4_moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).
GeneDx	RCV000185742	SCV000238670	pathogenic	not provided	2020-12-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20060901, 21932095, 9973285, 17999356, 32655480, 32447334, 31589614)
Invitae	RCV000412436	SCV000654958	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-31	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 185 of the ACADVL protein (p.Gly185Ser). This variant is present in population databases (rs545215807, gnomAD 0.006%). This missense change has been observed in individual(s) with diminished VLCAD protein expression and enzyme activity (PMID: 17999356, 20060901). ClinVar contains an entry for this variant (Variation ID: 203595). 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%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000412436	SCV000883349	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-12-23	criteria provided, single submitter	clinical testing	The ACADVL c.553G>A, p.Gly185Ser variant (rs545215807), also known as Gly145Ser, has been reported in multiple individuals with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen 1999, Gobin-Limballe 2007, Yamaguchi 2012). Multiple affected individuals with this variant were also found to carry a second pathogenic variant (Gobin-Limballe 2007, Yamaguchi 2012). The p.Gly185Ser variant is listed in ClinVar (Variation ID: 203595) and is observed on only three chromosomes in the Genome Aggregation Database (3/251456 alleles). The glycine at position 185 is highly conserved (Alamut v2.10), and it occurs in the substrate binding cavity of the VLCAD enzyme (Hoffman 2012). Functional characterization of patient fibroblasts carrying this variant indicates a substantial decrease in VLCAD protein levels (Andresen 1999, Gobin-Limballe 2010) and enzymatic activity compared to wildtype (Gobin-Limballe 2007, Hoffman 2012). Based on available information, the p.Gly185Ser variant is considered to be pathogenic. References: Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999; 64(2):479-94. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007; 81(6):1133-43. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010; 1802(5):478-84. 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. Yamaguchi S et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. Mol Genet Metab. 2012; 107(1-2):87-91.
CeGaT Center for Human Genetics Tuebingen	RCV000185742	SCV001246296	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000412436	SCV001364892	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.553G>A (NP_000009.1:p.Gly185Ser) [GRCH38: NC_000017.11:g.7221613G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Genome-Nilou Lab	RCV000412436	SCV001810246	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-07-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412436	SCV002060179	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-11-16	criteria provided, single submitter	clinical testing	NM_000018.3(ACADVL):c.553G>A(G185S) is a missense variant classified as likely pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. G185S has been observed in cases with relevant disease (PMID: 31620161, 32655480, 22841441, 21932095, 17999356, 9973285). Functional assessments of this variant are not available in the literature. G185S has been observed in population frequency databases (gnomAD: EAS 0.006%). In summary, NM_000018.3(ACADVL):c.553G>A(G185S) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
3billion	RCV000412436	SCV003842007	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000203595). A different missense change at the same codon (p.Gly185Ala) has been reported to be associated with ACADVL related disorder (ClinVar ID: VCV000450792). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003416111	SCV004113809	likely pathogenic	ACADVL-related condition	2023-05-12	criteria provided, single submitter	clinical testing	The ACADVL c.553G>A variant is predicted to result in the amino acid substitution p.Gly185Ser. This variant has been reported, along with a second ACADVL variant, in patients with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) ranging from the severe neonatal onset form to later onset exercise-induced rhabdomyolysis (Gobin-Limballe et al. 2007. PubMed ID: 17999356; Yamaguchi et al. 2012. PubMed ID: 22841441; Musumeci et al. 2020. PubMed ID: 32655480). It was also reported in the heterozygous state without a second ACADVL variant in a patient with 29% residual enzyme activity (Hoffmann et al. 2012. PubMed ID: 21932095, described as p.G145S). In fibroblasts from patients carrying the p.Gly185Ser substitution along with a second ACADVL variant, enzyme activity and protein levels were greatly reduced (Gobin-Limballe et al. 2007. PubMed ID: 17999356; Gobin-Limballe et al. 2010. PubMed ID: 20060901). Based on structure mapping, the p.Gly185 amino acid is predicted to lie in a very hydrophobic pocket lining the enzyme acyl-CoA binding cavity, and it has been noted that substitution of glycine with a polar serine residue in this location could affect substrate binding (Gobin-Limballe et al. 2010. PubMed ID: 20060901). This variant has been interpreted as likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/203595/). Taken together, we interpret the c.553G>A (p.Gly185Ser) variant as likely pathogenic for autosomal recessive VLCADD.
Baylor Genetics	RCV000412436	SCV004213995	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000412436	SCV002088755	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-09-29	no assertion criteria provided	clinical testing