ClinVar Miner

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

gnomAD frequency: 0.00280  dbSNP: rs150140386
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) 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 RCV001704250 SCV000511944 benign not provided 2021-02-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23867825, 26385305, 27209629, 31031081)
Invitae RCV000544014 SCV000654917 benign Very long chain acyl-CoA dehydrogenase deficiency 2021-12-18 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 2022-02-01 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 individuals with an abnormal acylcarnitine profiles who also carried a pathogenic variant (Pena 2016, Tangeraas 2020). 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 codon 356 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.621). 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. PMID: 26385305. 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. PMID: 27209629. Tangeraas T et al. Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses. Int J Neonatal Screen. 2020 Jun 27;6(3):51. PMID: 33123633.
Illumina Laboratory Services,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 2022-05-03 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 (IPR009075) 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 0.00085 in 250672 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-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 or African-American origin. c.1066A>G has been reported in the literature in individuals with abnormal newborn screening results, hypoglycemia or fatty acid oxidation defects (Ndukwe_2013, Miller_2015, Pena_2016, Hesse_2018, Tangeraas_2020). These reports do 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 ClinVar submitters (evaluation after 2014) cite the variant as benign and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. 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
Myriad Women's Health, Inc. RCV000544014 SCV002060266 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2021-10-27 criteria provided, single submitter clinical testing NM_000018.3(ACADVL):c.1066A>G(I356V) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. I356V has been observed in cases with relevant disease (PMID: 20480395, 23867825, 27209629, 30194637, 33123633). Functional assessments of this variant are not available in the literature. I356V has been observed in population frequency databases (gnomAD: AFR 0.98%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1066A>G(I356V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

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