Submissions for variant NM_000018.4(ACADVL):c.1153C>T (p.Arg385Trp)

gnomAD frequency: 0.00004  dbSNP: rs745832866

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173952	SCV000225144	uncertain significance	not provided	2015-04-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000668844	SCV000793516	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-08-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000668844	SCV000915778	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2018-11-20	criteria provided, single submitter	clinical testing	The ACADVL c.1156C>T (p.Arg385Trp) is a missense variant that has been reported in at least five studies and found in at least five individuals with VLCAD deficiency, including a sibling pair, in a compound heterozygous state with a unique missense variant in each case (Boneh et al. 2006; Wasibren et al. 2013; Yamamoto et al. 2015; Evans et al. 2016; Merinero et al. 2017). This variant was inherited from the unaffected mother in a heterozygous state (Merinero et al. 2017) and is reported at a frequency of 0.000208 in the Latino population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg386Cys variant is classified as likely pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000668844	SCV001156591	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-07-22	criteria provided, single submitter	clinical testing	The ACADVL c.1153C>T; p.Arg385Trp variant (rs745832866), also reported as Arg345Trp, has been described in multiple individuals in association with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD; Boneh 2006, Merinero 2018, Ohashi 2004, Yamamoto 2015). It contains an entry in ClinVar (Variation ID: 193786), and is observed at a low overall frequency of 0.004% (10/251484 alleles) in the Genome Aggregation Database. The arginine at codon 385 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, recombinant ACADVL protein harboring the p.Arg385Trp substitution showed a reduction in enzyme activity comparted to wildtype (Ohashi 2004). Based on available information, this variant is considered likely pathogenic. REFERENCES Boneh et al. VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. Mol. Genet. Metab. 2006; 88(2): 166-170. Merinero B et al. Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. JIMD Rep. 2018;39:63-74. Ohashi et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004; 62(12): 2209-2213. Yamamoto H et al. Successful management of pregnancy with very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Obstet Gynaecol Res. 2015 Jul;41(7):1126-8.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000668844	SCV001364916	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1153C>T (NP_000009.1:p.Arg385Trp) [GRCH38: NC_000017.11:g.7223208C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 15210884. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
GeneDx	RCV000173952	SCV001777338	uncertain significance	not provided	2020-09-10	criteria provided, single submitter	clinical testing	Reported previously in the presence of a second ACADVL variant in two individuals with abnormal newborn screen results who were not reported to be affected (Boneh et al., 2006; Merinero et al., 2017); Reported in the presence of a second ACADVL variant in an individual with mild intellectual disability and sporadic choreo-athetoid movements, who also complained of recurrent episodes of rhabdomyolysis triggered by exercise. A second molecular diagnosis was established that partially explained his phenotype (Musumeci et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15210884, 32655480, 23798014, 26385305, 25655073, 27246109, 16488171, 28755359)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668844	SCV002050776	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-12-06	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1153C>T (p.Arg385Trp) 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 4e-05 in 251484 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (4e-05 vs 0.0029), allowing no conclusion about variant significance. c.1153C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example Ohashi_2004, Merinero_2018, Musumeci_2020, Chen_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ohashi_2004, Chen_2020). The most pronounced variant effect results in a reduction in enzyme activity compared to wild type. Consistently, another recent study utilized this variant as a positive control to demonstrate a barely detectable level of fatty acid oxidation (FAO) activity as determined by overexpression of the recombinant HAtagged mutant proteins in HEK293T cell lines (Chen_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic/pathogenic, n=4; VUS, n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000668844	SCV002164258	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 385 of the ACADVL protein (p.Arg385Trp). This variant is present in population databases (rs745832866, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23798014, 25655073, 28755359, 32655480). This variant is also known as R345W. ClinVar contains an entry for this variant (Variation ID: 193786). 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: 15210884). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000668844	SCV004214029	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927590	SCV004745594	pathogenic	ACADVL-related condition	2023-12-20	criteria provided, single submitter	clinical testing	The ACADVL c.1153C>T variant is predicted to result in the amino acid substitution p.Arg385Trp. This variant has been reported in the compound heterozygous or homozygous states in individuals with very long chain acyl-CoA dehydrogenase deficiency (see, for example, Ohashi et al. 2004. PubMed ID: 15210884; Merinero et al. 2017. PubMed ID: 28755359; Chen et al. 2020. PubMed ID: 33150772). In vitro experimental studies suggest this variant impacts protein function (Ohashi et al. 2004. PubMed ID: 15210884; Chen et al. 2020. PubMed ID: 33150772). This variant is reported in 0.020% of alleles in individuals of Latino descent in a large population database. This variant is interpreted as pathogenic.
Natera, Inc.	RCV000668844	SCV001459250	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing