ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.848T>C (p.Val283Ala) (rs113994167)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000077925 SCV000602354 pathogenic not provided 2017-05-26 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077925 SCV000510857 pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing
Counsyl RCV000020081 SCV000485188 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2015-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077925 SCV000232892 pathogenic not provided 2015-10-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000020081 SCV000611159 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000077925 SCV000238638 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The V283A missense variant in the ACADVL gene has been reported previously in association withvery long chain acyl-CoA dehydrogenase (VLCAD) deficiency and accounts for approximately 20% ofpathogenic alleles in patients detected by newborn screening (Leslie, N. et al., 2014). V283A is usuallyassociated with a mild phenotype (Pena et al. 2016). Functional analysis found that V283A wasassociated with approximately 20% residual enzyme activity compared to wild type (Goetzman et al., 2007; Andresen et al., 1999). In summary, we interpret V283A to be a pathogenic variant.
GeneReviews RCV000020081 SCV000040379 pathologic Very long chain acyl-CoA dehydrogenase deficiency 2011-09-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000020081 SCV000593009 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-03-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000020081 SCV000406318 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2017-10-18 criteria provided, single submitter clinical testing The ACADVL c.848T>C (p.Val283Ala) variant, also referred to as c.917T>C (p.Val306Ala), is one of the most common pathogenic variants and accounts for approximately 20% of disease-causing alleles among individuals with VLCAD deficiency ascertained by newborn screening (Leslie et al. 2014). Across a selection of the available literature, the p.Val283Ala variant was identified in a total of 20 individuals with VLCAD deficiency, including two homozygotes, 17 compound heterozygotes, and one heterozygote (Andresen et al. 1996; Andresen et al. 1999; Shchelochkov et al. 2009; Coughlin et al. 2010; McGoey et al. 2011; Schiff et al. 2013; Merritt et al. 2014). The phenotypic spectrum of these individuals ranged from asymptomatic to severe. The variant was absent from 51 control individuals, but is reported at a frequency of 0.00241 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression studies in prokaryotic and mammalian cells showed that the p.Val283Ala variant had enzyme activity of 20%-25% of the wild type (Andresen et al. 1999; Goetzman et al. 2007). Based on the evidence, the p.Val283Ala variant is classified as pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000020081 SCV000693967 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-01-22 criteria provided, single submitter clinical testing Variant summary: The c.848T>C in ACADVL gene is a missense variant that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is present in the broad control population dataset of ExAC at a low frequency (0.14%), which does not exceed the maximum frequency for a pathogenic variant in ACADVL gene (0.29%), suggesting this variant is not a common polymorphism. The variant has been reported in multiple affected individuals presented with Very-long-chain acyl-coenzyme A dehydrogenase deficiency. It is one of the most common pathogenic alleles that accounts for approximately 20% of all pathogenic alleles among individuals detected by newborn screening. This variant is considered to be a mild mutation with residual enzymatic activity ranging between 10%-22%. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers. Taking together, the variant was classified as Pathogenic.
Invitae RCV000020081 SCV000654971 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 283 of the ACADVL protein (p.Val283Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs113994167, ExAC 0.2%). This variant has been reported as homozygous or in combination with other ACADVL variants in individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and is associated with a wide range of clinical presentations (PMID: 14517516, 17999356, 20107901). This variant is also known as V243A in the literature. ClinVar contains an entry for this variant (Variation ID: 21025). Peripheral cells from homozygous patients have been reported with elevations of C14:1 and low VLCAD enzymatic activity (PMID: 26385305). Experimental studies have also shown that this variant impairs the enzymatic activity (~20% of wildtype) of the ACADVL protein in vitro (PMID: 17374501, 9973285). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000020081 SCV000494238 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-06-27 criteria provided, single submitter clinical testing The c.848T>C (p.Val283Ala) missense variant in the ACADVL gene has been previously reported in numerous individuals affected with VLCAD deficiency with both the mild and severe types depending on the other variants the patients harbored, and is thus considered a common pathogenic variant associated with VLCAD deficiency (Andresen et al., 1996; Andresen et al., 1999; Boneh et al., 2006; Coughlin et al., 2010; Hoffmann et al., 2012; Miller et al., 2015). This variant is often observed in trans with other pathogenic variants in affected individuals (Boneh et al., 2006; Coughlin et al., 2010; Hoffmann et al., 2012). Furthermore, functional assays both in vitro and from patients have demonstrated that this variant resulted in reduced residual enzymatic activity (Andresen et al., 1999; Goetzman et al., 2007; Hoffmann et al., 2012). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.128%; 1000 Genomes = NA; and ExAC = 0.24%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.22; CADD = 21.8; SIFT = 0.0). Multiple reputable diagnostic laboratories have classified this variant as Pathogenic (Emory, GeneDx). Therefore, this collective evidence supports the classification of the c.848T>C (p.Val283Ala) as a Pathogenic variant for VLCAD deficiency. We have confirmed this finding in our laboratory using Sanger sequencing.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000020081 SCV000711421 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-08-25 criteria provided, single submitter clinical testing The p.Val283Ala variant in ACADVL has been reported in several patients with ver y long chain acyl-CoA dehydrogenase deficiency in the homozygous or compound het erozygous state (Andresen 1996, Andresen 1999, Coughlin 2010, Hoffmann 2012, Sch woerer 2015). It has been generally associated with a milder phenotype (Spiekerk oetter 2009). This variant has also been identified in 0.24% (160/66534) of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP 113994167). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequen cy. In addition, in vitro functional studies provide some evidence that the p.Va l283Ala variant may impact protein function (Andresen 1999, Goetzman 2007). In s ummary, this variant meets criteria to be classified as pathogenic for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner based upon case studies, low frequency in controls and functional evidence.

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