ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.664G>A (p.Gly222Arg) (rs398123091)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077922 SCV000109751 likely pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
Counsyl RCV000169301 SCV000220620 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-08-21 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077922 SCV000281258 likely pathogenic not provided 2014-06-27 criteria provided, single submitter clinical testing
GeneDx RCV000077922 SCV000491232 likely pathogenic not provided 2016-11-22 criteria provided, single submitter clinical testing The G222R missense variant in the ACADVL gene has been reported previously in patients with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Voermans et al. 2006; Gobin-Limballe et al. 2007; Li et al. 2015). The G222R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G222R variant is a non-conservative amino acid substitution, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, G222 is the first residue of the conserved Gly-Ser-Asp segment where it is believed that substitution of Glycine by a bulky, charged Arginine may change the conformation of the VLCAD protein and disrupt cofactor binding (Gobin-Limballe et al. 2010). In summary, we interpret G222R to be likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000169301 SCV001158613 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-09-11 criteria provided, single submitter clinical testing The ACADVL c.664G>A; p.Gly222Arg variant (rs398123091) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Gobin-Limballe 2010, Voermans 2006). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 92289), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 222 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this nucleotide position (c.664G>C; p.Gly222Arg) has been reported in individuals with VLCADD (Zhang 2014). Glycine 222 is part of a conserved GSD segment critical for cofactor binding, and p.G222R is predicted to disrupt this interaction (Gobin-Limballe 2010). Furthermore, in vitro functional analyses demonstrate reduced ACADVL protein levels (Gobin-Limballe 2010). Based on available information, the c.664G>A; p.Gly222Arg variant is considered to be pathogenic. References: 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 May;1802(5):478-84. Voermans NC et al. Rhabdomyolysis caused by an inherited metabolic disease: very long-chain acyl-CoA dehydrogenase deficiency. Am J Med. 2006 Feb;119(2):176-9. Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000169301 SCV001364899 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.664G>A (NP_000009.1:p.Gly222Arg) [GRCH38: NC_000017.11:g.7221993G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Invitae RCV000169301 SCV001419813 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 222 of the ACADVL protein (p.Gly222Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in or in combination with another ACADVL variant in several individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 20060901, 25652019, 26182500). This variant is also known as G245R in the literature. ClinVar contains an entry for this variant (Variation ID: 92289). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). For these reasons, this variant has been classified as Pathogenic. 5

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