ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1066A>G (p.Ile356Val) (rs150140386)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173615 SCV000224739 benign not specified 2014-10-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000173615 SCV000301513 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000173615 SCV000511944 likely benign not specified 2017-08-23 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000544014 SCV000654917 benign Very long chain acyl-CoA dehydrogenase deficiency 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000544014 SCV000789148 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-01-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000544014 SCV001156590 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-04-18 criteria provided, single submitter clinical testing The c.1066A>G; p.Ile356Val variant (rs150140386) is reported in the literature in multiple patients with abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, though its clinical significance was not determined (Miller 2015). In addition, this variant has been observed in an asymptomatic individual with an abnormal acylcarnitine profile who also carried a pathogenic variant (Pena 2016). However, the p.Ile356Val variant is found in the African population with an overall allele frequency of 0.98% (244/24934 alleles, including three homozygotes) in the Genome Aggregation Database. The isoleucine at residue 356 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the significance of the p.Ile356Val variant is uncertain at this time. References: Miller M 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.
Illumina Clinical Services Laboratory,Illumina RCV000544014 SCV001285767 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173615 SCV001362320 likely benign not specified 2019-01-11 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1066A>G (p.Ile356Val) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 276458 control chromosomes, predominantly at a frequency of 0.0097 within the African subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.1066A>G, has been reported in the literature in individuals with abnormal newborn screening results, hypoglycemia or fatty acid oxidation defects (Miller_2015, Ndukwe_2013, Pena_2016, Hesse_2018). This report does not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Hesse_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign x2, VUS x1). Based on the evidence outlined above, the variant was classified as likely benign.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000544014 SCV001365181 benign Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1066A>G (NP_000009.1:p.Ile356Val) [GRCH38: NC_000017.11:g.7222854A>G] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2

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