ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1349G>A (p.Arg450His) (rs118204016)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000724571 SCV000884952 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing The ACADVL c.1349G>A; p.Arg450His variant (rs118204016), also known as Arg410His for traditional nomenclature, is reported multiple times in the literature in association with VLCAD deficiency and is reported both in the homozygous and compound heterozygous states in affected individuals (Andresen 1999, Fukao 2001, Gobin-Limballe 2010, Kang 2018, Ohashi 2004, Smelt 1998, Zhang 2014). Additionally, functional analyses of the variant protein show decreased expression and enzymatic activity (Fukao 2001, Smelt 1998). This variant is reported in ClinVar (Variation ID: 1634) and found in the general population with a low overall allele frequency of 0.003% (8/277108 alleles) in the Genome Aggregation Database. The arginine at codon 450 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Fukao T et al. Myopathic form of very-long chain acyl-coa dehydrogenase deficiency: evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl. Pediatr Res. 2001 Feb;49(2):227-31. 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. Kang E et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 2018 Mar 8;18(1):103. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13. Smelt AH et al. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol. 1998 Apr;43(4):540-4. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724571 SCV000225986 likely pathogenic not provided 2015-01-27 criteria provided, single submitter clinical testing
Invitae RCV000001701 SCV000654930 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2017-04-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 450 of the ACADVL protein (p.Arg450His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs118204016, ExAC no frequency). This variant has been reported in several individuals affected with very long chain acyl-CoA dehydrogenase deficiency. Some of these individuals have been shown to be homozygous for this variant or compound heterozygous (in trans) with other deleterious ACADVL variants (PMID: 9546340, 11158518, 15210884, 24801231). This variant is also known as R410H in the literature. ClinVar contains an entry for this variant (Variation ID: 1634). Experimental studies have shown that this missense change reduces ACADVL enzymatic activity (PMID: 11158518). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001701 SCV000021857 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2001-02-01 no assertion criteria provided literature only

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