ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg) (rs398123079)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077898 SCV000109727 uncertain significance not provided 2015-07-02 criteria provided, single submitter clinical testing
GeneDx RCV000077898 SCV000238642 uncertain significance not provided 2018-04-18 criteria provided, single submitter clinical testing The M334R variant has been reported in multiple individuals with an abnormal newborn screening result for VLCAD deficiency in whom a second ACADVL variant was not identified (Miller et al. 2015). M334R has also been reported in an asymptomatic individual who was diagnosed with VLCAD deficiency via molecular testing and acylcarnitine profile analysis following an abnormal newborn screening result. This individual also had a second missense variant identified in the ACADVL gene although the phase of the two variants was not reported (Pena et al., 2016) The M334R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). M334R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, based on the currently available information, it is unclear whether the M334R variant pathogenic or a rare benign variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077898 SCV000280923 uncertain significance not provided 2015-02-19 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Counsyl RCV000668860 SCV000793533 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-08-18 criteria provided, single submitter clinical testing
Invitae RCV000668860 SCV000815383 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-08-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 334 of the ACADVL protein (p.Met334Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs398123079, ExAC 0.005%). This variant has been observed to segregate with VLCAD deficiency in a family (Invitae) and has been reported in an unrelated individual with features of VLCAD deficiency (PMID: 27209629). ClinVar contains an entry for this variant (Variation ID: 92270). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000668860 SCV001160513 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-04-19 criteria provided, single submitter clinical testing The ACADVL c.1001T>G; p.Met334Arg variant (rs148584617) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase deficiency (Miller 2015, Pena 2016). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 92270), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 334 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Met334Arg variant is uncertain at this time. References: 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. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81.
Integrated Genetics/Laboratory Corporation of America RCV001174775 SCV001338104 uncertain significance not specified 2020-01-21 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1001T>G (p.Met334Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain 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 1.6e-05 in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1001T>G has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency following newborn screening results (Miller_2015, Pena_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000668860 SCV001365225 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1001T>G (NP_000009.1:p.Met334Arg) [GRCH38: NC_000017.11:g.7222789T>G] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3

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