Submissions for variant NM_000018.4(ACADVL):c.520G>A (p.Val174Met)

gnomAD frequency: 0.00009  dbSNP: rs369560930

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000077919	SCV000231986	pathogenic	not provided	2015-03-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000077919	SCV000518399	likely pathogenic	not provided	2017-09-26	criteria provided, single submitter	clinical testing	The V174M missense variant has been previously reported in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Tajima et al., 2008; Gobin-Limballe et al., 2010; Andresen et al., 1999). V174M is reported to likely be a mild ACADVL variant as fibroblasts homozygous for V174M showed enzyme activity equivalent to 27% of normal levels (Gobin-Limballe et al., 2010). The V174M variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V174M substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, we interpret V174M as likely pathogenic.
Invitae	RCV000179696	SCV000773888	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 174 of the ACADVL protein (p.Val174Met). This variant is present in population databases (rs369560930, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 17999356, 18670371, 23430950, 26881790, 28755359). This variant is also known as p.Val134Met. ClinVar contains an entry for this variant (Variation ID: 92286). 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	RCV000179696	SCV000883332	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-01-01	criteria provided, single submitter	clinical testing	The ACADVL c.520G>A; p.Val174Met variant (rs369560930), also known as Val134Met, has been identified in individuals with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, who are compound heterozygous or homozygous carriers (Andresen 1999, Diekman 2016, Gobin-Limballe 2010, Tajima 2008). It is reported as likely pathogenic and pathogenic in ClinVar (Variation ID: 92286) and is observed in the general population at a low overall frequency of 0.006% (17/277192) in the Genome Aggregation Database. The valine at codon 174 is moderately conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious. Additionally, functional studies of a patient’s fibroblasts with homozygous p.Val174Met demonstrated FAO capacities that were 27% of the normal level (Gobin-Limballe 2010). Based on available information, this variant is considered 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. Diekman E et al. Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. PLoS One. 2016 Feb 16;11(2):e0147818. 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. Tajima G et al. Development of a new enzymatic diagnosis method for very-long-chain Acyl-CoA dehydrogenase deficiency by detecting 2-hexadecenoyl-CoA production and its application in tandem mass spectrometry-based selective screening and newborn screening in Japan. Pediatr Res. 2008 Dec;64(6):667-72.
Baylor Genetics	RCV000179696	SCV001163797	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179696	SCV001362323	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-08-18	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.520G>A (p.Val174Met) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (4.4e-05 vs 0.0029), allowing no conclusion about variant significance. c.520G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andersen_1999, Gobin-Limballe_2007, Tajima_2008, Zweers_2012, Merinero_2018). 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. The most pronounced variant effect results in 10%-<30% of normal activity in the homozygous state and its characterization as a mild-mutation (Gobin-Limballe_2010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000179696	SCV001364891	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.520G>A (NP_000009.1:p.Val174Met) [GRCH38: NC_000017.11:g.7221580G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Revvity Omics, Revvity	RCV000179696	SCV002021140	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-03-17	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000179696	SCV002097338	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000077919	SCV004226686	pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing	PP4, PM2, PM3_strong, PS3
Counsyl	RCV000179696	SCV000486666	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2016-07-21	no assertion criteria provided	clinical testing