ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.865G>A (p.Gly289Arg) (rs200788251)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489455 SCV000576558 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing The G289R missense variant has been reported previously in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in individuals who were also heterozygous for a second variant in the ACADVL gene (Spiekerkoetter et al., 2003; Schiff et al., 2013; Takahashi et al., 2014). Expression of G289R in E. coli found that it is associated with approximately 15% residual enzyme activity (Schiff et al., 2013). The G289R variant is observed in 28/126,620 (0.022%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). In summary, we interpret this variant as pathogenic.
Invitae RCV000408960 SCV000820769 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 289 of the ACADVL protein (p.Gly289Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200788251, ExAC 0.02%). This variant has been reported in combination with another ACADVL variant in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27246109, 27209629, 14517516, 23480858). This variant is also known in the literature as Gly249Arg. ClinVar contains an entry for this variant (Variation ID: 370981). Experimental studies have shown that this missense change causes a large reduction in ACADVL enzyme activity (PMID: 23480858). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000408960 SCV000915776 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-01-22 criteria provided, single submitter clinical testing Across a selection of the available literature, the ACADVL c.865G>A (p.Gly289Arg) variant has been reported in a compound heterozygous state in at least six individuals identified as having VLCAD deficiency through newborn screening (Spiekerkoetter et al. 2003; Schiff et al. 2013; Waisbren et al. 2013; Pena et al. 2016; Evans et al. 2016). Several of these individuals were described as asymptomatic, however, speech/language and motor delays, autistic spectrum behavior and relative weakness in the fine motor area were reported in two individuals after at least two years of follow-up (Waisbren et al. 2013). Analysis of 693 unrelated individuals with a positive newborn screening result for VLCAD deficiency, identified the p.Gly289Arg variant on six alleles from affected individuals (Miller et al. (2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Fibroblasts from one individual who was compound heterozygous for the p.Gly289Arg variant, exhibited no detectable enzyme activity and absent protein expression based on Western blot analysis. In vitro expression analyses in E. coli showed that the p.Gly289Arg variant displayed 15% of wildtype activity and reduced protein expression (Schiff et al. 2013). Based on the collective evidence, the p.Gly289Arg 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.
Counsyl RCV000408960 SCV000486424 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-05-27 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.