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

gnomAD frequency: 0.00001  dbSNP: rs118204016

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000001701	SCV002769745	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-14	reviewed by expert panel	curation	The c.1349G>A (p.Arg450His) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 450. At least one individual with this variant displayed reduced VLCAD activity, which is specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 11158518). This variant has been confirmed in trans to at least one likely pathogenic variant, not confirmed in trans to distinct likely pathogenic variants, and has been identified in the homozygous state in 2 individuals (PM3_Strong, PMID: 29519241, 15210884, 11158518, 9546340). The highest population minor allele frequency in gnomAD v2.0 is 0.00025 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021)
Eurofins Ntd Llc (ga)	RCV000724571	SCV000225986	likely pathogenic	not provided	2015-01-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001701	SCV000654930	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACADVL protein (p.Arg450His). This variant is present in population databases (rs118204016, gnomAD 0.03%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9546340, 11158518, 15210884, 24801231). This variant is also known as R410H. ClinVar contains an entry for this variant (Variation ID: 1634). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 11158518). For these reasons, this variant has been classified as Pathogenic.
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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000001701	SCV001364921	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1349G>A (NP_000009.1:p.Arg450His) [GRCH38: NC_000017.11:g.7223984G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
GeneDx	RCV000724571	SCV001811368	pathogenic	not provided	2019-07-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 31130284, 30840296, 11158518, 20060901, 24801231, 29519241, 28980192, 29552494, 27246109, 25652019, 9973285, 9546340, 15210884)
Baylor Genetics	RCV000001701	SCV004210767	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-02-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000001701	SCV004235433	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001701	SCV004241874	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1349G>A (p.Arg450His) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251342 control chromosomes (gnomAD). c.1349G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Fukao_2001, Osawa_2022), and some were compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Fukao_2001). Seven submitters, including a ClinGen expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000001701	SCV004801148	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-14	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000001701	SCV004847467	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-21	criteria provided, single submitter	clinical testing	The p.Arg473His variant in ACADVL has been reported in the homozygous state in at least 2 individuals and in the compound heterozygous state in at least 7 individuals with very long chain acyl-CoA dehydrogenase deficiency, at least one of whom showed reduced enzyme activity consistent with the condition. In at least 4 of these individuals, the p.Arg473His was identified with a potentially disease causing variant in ACADVL, and the variants were confirmed to be in trans in at least 1 individual (Andresen 1999 PMID: 9973285, Fukao 2001 PMID: 11158518, Smelt 1998 PMID: 9546340, Ohashi 2004 PMID: 15210884, Osawa 2022 PMID: 35400565). This variant has also been identified in 0.01% (6/44888) of East Asian chromosomes by gnomAD, including 1 homozygote in the South Asian population (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies of enzymatic activity and protein expression provide some evidence that this variant impacts protein function (Fukao 2001 PMID: 11158518; Ohashi 2004 PMID: 15210884; Osawa 2022 PMID: 35400565) and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as likely pathogenic on Dec 14, 2022 by the ClinGen-approved ACADVL Variant Curation Expert Panel (Variation ID 1634). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting, PP4, PP3, PM2_Supporting.
OMIM	RCV000001701	SCV000021857	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2001-02-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003625	SCV001162036	pathogenic	Abnormal circulating enzyme concentration; Rhabdomyolysis		no assertion criteria provided	research
Natera, Inc.	RCV000001701	SCV001459255	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing