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

gnomAD frequency: 0.00280  dbSNP: rs150140386

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000544014	SCV002576747	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-04-11	reviewed by expert panel	curation	The c.1066A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 356 (p.Ile356Val). Several individuals with this variant were identified by newborn screen, but this information is insufficient to use toward classification (PMID: 30194637, 26385305, 23867825, 31031081, 27209629). One individual did display C14:1 level of 0.83, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 31031081). At least one of these individuals carried an additional likely pathogenic variant not confirmed to be in trans, but this does not meet the criteria to be counted toward PM3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009786 in the African population with 3 total homozygotes, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.621, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. In summary, this variant meets the criteria to be classified as variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on April 11, 2023.
Eurofins Ntd Llc (ga)	RCV000173615	SCV000224739	benign	not specified	2014-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544014	SCV000654917	benign	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-31	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	2022-05-20	criteria provided, single submitter	clinical testing	The ACADVL c.1066A>G; p.Ile356Val variant (rs150140386) is reported in the literature in multiple individuals with abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, though its clinical significance was not determined (Miller 2015). This variant has been observed in asymptomatic individuals with abnormal acylcarnitine profiles who also carried a pathogenic variant (Pena 2016, Tangeraas 2020). Additionally, it has been reported in a symptomatic individual with VLCAD deficiency (Rovelli 2019). This variant is reported in ClinVar (Variation ID: 193541). It is found in the African/African American population with an allele frequency of 0.98% (244/24934 alleles, including 3 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. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. 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 Genetics, 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.
Revvity Omics, Revvity	RCV000544014	SCV004238915	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-14	criteria provided, single submitter	clinical testing