Submissions for variant NM_000018.4(ACADVL):c.1844G>A (p.Arg615Gln)

gnomAD frequency: 0.00244  dbSNP: rs148584617

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000193309	SCV003936886	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-27	reviewed by expert panel	curation	The c.1844G>A variant in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 615 (p.Arg615Gln), also called Arg575Gln in the processed peptide. The variant has been identified in individuals identified by positive newborn screen, or identified in individuals with suspected very long chain acyl-CoA dehydrogenase (VLCAD) deficiency that was not confirmed biochemically, but this information is insufficient to use toward classification (PMID: 10077518, 17999356, 27209629, 21932095, 26453363). The variant has been reported to occur in individuals who also carried a distinct ACADVL variant not confirmed in trans; however, since none of these individuals met PP4, the ACADVL VCEP could not count these toward PM3 evidence (PMID: 17999356, 21932095, 27209629). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.003654 in the European (non-Finnish) population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.0035) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.397, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4 (ACADVL VCEP specifications version 1; approved November 8, 2021).
Eurofins Ntd Llc (ga)	RCV000176020	SCV000227603	uncertain significance	not provided	2018-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000176020	SCV000238661	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28755359, 27884173, 21932095, 27209629, 10077518, 17999356, 30194637, 34485012, 32778825, 34426522, 35281663, 35626289, 25087612, 26453363)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000193309	SCV000602356	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-11-09	criteria provided, single submitter	clinical testing	The ACADVL p.Arg615Gln variant (rs148584617; ClinVar variation ID: 195448) has been previously identified by our laboratory, and is described in the literature in multiple patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Gobin-Limballe 2007, Mathur 1999, Hoffmann 2012, Diekman 2016, Pena 2016). However the exact contribution of this variant to the clinical presentation of these patients is unclear. The enzyme activity in cells isolated from patients with VCLAD was reported to range from 21% of control activity (Hoffmann 2012) to 40% (Diekman 2016) to be indistinguishable from control activity (Gobin-Limballe 2007) for p.Arg615Gln when in trans with different ACADVL variants. And at least one study identified this variant in two individuals who failed newborn screening, but had not developed symptoms at age 2 (Diekman 2016). Furthermore, this variant is found in the general population with an overall allele frequency of 0.27% (758/282,554 alleles, including 4 homozygotes) in the Genome Aggregation Database. The arginine at codon 615 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.397). Due to conflicting information, the clinical significance of the p.Arg615Gln variant is uncertain at this time. References: Diekman E et al. The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency. JIMD Rep. 2016;27:101-6. PMID: 26453363. Gobin-Limballe 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): 1133-1143. PMID: 17999356. Hoffmann et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2): 269-277. PMID: 21932095. Mathur et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10): 1337-1343. PMID: 10077518. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PubMed: 27209629. Tabor et al. Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Am J Hum Genet. 2014; 95(2): 183-193. PubMed: 25087612.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000193309	SCV000654946	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000176020	SCV000780557	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ACADVL: BP4, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000176020	SCV000782653	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	BS1
Baylor Genetics	RCV000193309	SCV001163428	likely benign	Very long chain acyl-CoA dehydrogenase deficiency		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000193309	SCV001282893	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000193309	SCV001365217	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1844G>A (NP_000009.1:p.Arg615Gln) [GRCH38: NC_000017.11:g.7224973G>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: BP4
Institute of Human Genetics, University of Leipzig Medical Center	RCV000193309	SCV001440708	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000193309	SCV001737187	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307434	SCV002600383	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1844G>A (p.Arg615Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251176 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. An additional 5 homozygous occurrences have been reported in the literature in individuals with lack of phenotype (Abouelhoda_2016, Kars_2021). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) phenotype (0.0029), suggesting that the variant is a benign polymorphism. c.1844G>A has been reported in the literature as a biallelic genotype in individuals with mild forms of VLCAD deficiency and in individuals identified through Newborn Screening who were asymptomatic (e.g. Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016, Pena_2016). Residual enzymatic activities in compound heterozygous individuals carrying pathogenic variants in trans ranged from 21%, to 40% and up to similar activity to controls (Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016). In one simple heterozygous individual with the variant, residual enzymatic activity was measured at 39% (Hoffmann_2012), with the authors concluding from their study that individuals with a residual enzyme activity >20% present with a biochemical phenotype but likely remain asymptomatic throughout life. The variant was found to co-occur in cis with a pathogenic variant in one homozygous and one compound heterozygous individuals who had symptoms of VLCAD (Merinero_2018). Eleven ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, and four as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000193309	SCV000223917	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2014-10-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000193309	SCV001455191	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2020-06-19	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000176020	SCV001799068	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000176020	SCV001932461	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000176020	SCV001958927	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000176020	SCV001973985	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754333	SCV005352046	likely benign	ACADVL-related disorder	2024-08-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).