Submissions for variant NM_000018.4(ACADVL):c.1376G>A (p.Arg459Gln)

gnomAD frequency: 0.00003  dbSNP: rs751995154

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000412089	SCV002576751	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-08-09	reviewed by expert panel	curation	The c.1376G>A variant is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 459 (p.Arg459Gln). This variant has been reported in at least 11 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, with two individuals displaying both reduced VLCAD activity and increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 30194637; PMID: 21429517; PMID: 19327992). In these individuals, the variant was detected three times in the homozygous state plus 1 confirmed in-trans and 5 not confirmed in-trans with the pathogenic variant c.848T>C (PM3_strong; PMID: 30194637; PMID: 21429517). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004646 in the European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant is located in a well-studied dimerization domain which is critical for the protein's dimer interaction (PM1; PMID: 14517516). The computational predictor REVEL gives a score of 0.864, 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 pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate; PM3_Strong; PM2_Supporting; PM1; PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).
GeneDx	RCV000185726	SCV000238652	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21429517, 25214167, 32710939, 14517516, 26385305, 23798014, 19327992, 31589614, 34106991)
Counsyl	RCV000412089	SCV000487128	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2016-10-12	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414939	SCV000492896	likely pathogenic	Myopathy; Rhabdomyolysis	2015-01-23	criteria provided, single submitter	clinical testing
Invitae	RCV000412089	SCV000654932	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 459 of the ACADVL protein (p.Arg459Gln). This variant is present in population databases (rs751995154, gnomAD 0.005%). This missense change has been observed in individual(s) with VLCAD deficiency, several of them being clinically asymptomatic (PMID: 14517516, 19327992, 21429517, 23798014, 30194637). This variant is also known as p.Arg419Gln. ClinVar contains an entry for this variant (Variation ID: 203585). 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%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000412089	SCV000883346	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-01-05	criteria provided, single submitter	clinical testing	The ACADVL c.1376G>A; p.Arg459Gln variant (rs751995154), also known as p.Arg419Gln in traditional nomenclature, is reported in the literature in individuals with Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency (Laforet 2009, McGoey 2011, Miller 2015, Spiekerkoetter 2003, Waisbren 2013) and has been found in trans to other pathogenic variants (McGoey 2011, Spiekerkoetter 2003). Functional characterization of patient fibroblasts indicates significant reduction in VLCAD enzymatic activity (Laforet 2009). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 203585), and it is found on only eight chromosomes (8/282800 alleles) in the Genome Aggregation Database. The arginine at residue 459 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.864). Additional, another variant at the same codon (p.Arg459Trp) has been reported in individuals with VLCAD deficiency and is considered pathogenic (Andresen 1999, Miller 2015). Based on the above information, the p.Arg459Gln variant is considered to be pathogenic. References: Andresen B 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. PMID: 9973285. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009; 19(5):324-9. PMID: 19327992 McGoey R et al. Positive newborn screen in a normal infant of a mother with asymptomatic very long-chain Acyl-CoA dehydrogenase deficiency. J Pediatr. 2011; 158(6):1031-2. PMID: 21429517. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305 Spiekerkoetter U et al. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2003; 143(3):335-42. PMID: 14517516 Waisbren S et al. Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev. 2013; 17(3):260-8. PMID: 23798014.
Fulgent Genetics, Fulgent Genetics	RCV000412089	SCV000894149	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000412089	SCV001364928	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1376G>A (NP_000009.1:p.Arg459Gln) [GRCH38: NC_000017.11:g.7224011G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000412089	SCV001368576	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-04-02	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3.
Ambry Genetics	RCV002516958	SCV003733711	likely pathogenic	Inborn genetic diseases	2022-03-24	criteria provided, single submitter	clinical testing	The c.1376G>A (p.R459Q) alteration is located in exon 14 (coding exon 14) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 1376, causing the arginine (R) at amino acid position 459 to be replaced by a glutamine (Q). This alteration has been reported in the compound heterozygous and homozygous states in multiple individuals diagnosed with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Hesse, 2018; Lafor&ecirc;t, 2009; McGoey, 2011; Spiekerkoetter, 2003; Waisbren, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000412089	SCV003915825	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-04-14	criteria provided, single submitter	clinical testing	A heterozygous missense variant in exon 14 of the ACADVL gene that results in the amino acid substitution of Glutamine for Arginine at codon 459 (p.Arg459Gln) was detected. The observed variant has previously been reported in patients affected with VLCAD deficiency and functional characterization of patient fibroblasts indicates significant reduction in VLCAD enzymatic activity [PMID: 19327992]. The variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.003%, 0.002% and 0.003% in the gnomAD (v3.1), gnomdAD (v2), and topmed databases respectively. The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407682	SCV004110761	pathogenic	ACADVL-related condition	2024-01-25	criteria provided, single submitter	clinical testing	The ACADVL c.1376G>A variant is predicted to result in the amino acid substitution p.Arg459Gln. This variant has been reported in multiple individuals with very long chain acyl-CoA dehydrogenase deficiency (VLCADD), the majority of which have been identified via newborn screening (Spiekerkoetter et al. 2003. PubMed ID: 14517516; McGoey and Marble. 2011. PubMed ID: 21429517; Miller et al. 2015. PubMed ID: 26385305). Only a few patients with the c.1376G>A variant have been reported to be clinically symptomatic (Laforêt et al. 2009. PubMed ID: 19327992; Waisbren et al. 2013. PubMed ID: 23798014; Savarese et al. 2014. PubMed ID: 25214167). Available splicing prediction algorithms (Alamut Visual v2.11) indicate that this variant may create a novel splice acceptor site within ACADVL exon 14 (based on transcript NM_000018.3). However, it should be noted that such predictions are not equivalent to functional evidence. This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been classified as pathogenic by the ClinGen ACADVL Variant Curation Expert Panel and most submitters in clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/203585/). Based on collective evidence, this variant is interpreted as pathogenic.
Baylor Genetics	RCV000412089	SCV004183482	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000412089	SCV002088793	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-09	no assertion criteria provided	clinical testing