ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1844G>A (p.Arg615Gln) (rs148584617)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176020 SCV000227603 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing
GeneDx RCV000176020 SCV000238661 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing The R615Q variant in the ACADVL gene has been reported previously, with a second variant, in multiple individuals identified by a positive newborn screen. The majority of these individuals were clinically asymptomatic (Gobin-Limballe et al., 2007; Hoffmann et al., 2012; Diekman et al., 2016: Pena et al., 2016). The R615Q variant is observed in 746/276976 (0.27%) alleles from individuals in large population cohorts, including seven homozygotes (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R615Q as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000193309 SCV000602356 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-03-28 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% (746/276,976 alleles, including 7 homozygotes) in the Genome Aggregation Database. The arginine at codon 615 is moderately conserved considering 12 species (Alamut software version 2.11.0) and computational programs suggest this variant does not have a significant impact on ACADVL protein function (SIFT: tolerated, PoyPhen2: benign). Therefore, due to conflicting information in the literature regarding p.Arg615Gln, we cannot classify this variant with certainty. References: Diekman E et al. The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency. JIMD Rep. 2016;27:101-6. 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. 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. 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. 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.
Invitae RCV000193309 SCV000654946 likely benign Very long chain acyl-CoA dehydrogenase deficiency 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000176020 SCV000780557 likely benign not provided 2019-09-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000193309 SCV000782653 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-06-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000193309 SCV001163428 pathogenic Very long chain acyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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
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

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