Submissions for variant NM_000018.4(ACADVL):c.829_831del (p.Glu277del)

dbSNP: rs796051913

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185735	SCV000238663	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32778825, 20547398, 23169530, 30194637, 27209629, 23430948, 32061778)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527513	SCV000654970	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This variant, c.829_831del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu277del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs149680575, gnomAD 0.03%). This variant has been observed in individual(s) with VLCAD deficiency (PMID: 23169530, 23430948, 27209629, 30194637). ClinVar contains an entry for this variant (Variation ID: 203589). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000185735	SCV001501153	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000527513	SCV001652751	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000527513	SCV002021271	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-10-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000527513	SCV002041492	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-11-10	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.829_831delGAG (p.Glu277del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.00017 in 251448 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00017 vs 0.0029), allowing no conclusion about variant significance. c.829_831delGAG has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Spiekerkoetter_2012, Alhashem_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000527513	SCV002048617	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-20	criteria provided, single submitter	clinical testing	The ACADVL c.829_831delGAG; p.Glu277del (rs796051913), also known as Glu237del, has been detected in individuals affected with Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency and is described as a recurrent variant in positive newborn screening for VLCAD deficiency (Hesse 2018, Miller 2015, Pena 2016, Spiekerkoetter 2012). It is reported in ClinVar (Variation ID: 203589) and is observed in the general population at an overall frequency of 0.02% (46/277204 alleles) in the Genome Aggregation Database. This variant deletes a single glutamic acid residue leaving the rest of the protein in-frame. Additionally, other single amino acid deletions (Glu130del, Glu297del, Lys299del) have been reported in association with VLCAD deficiency (Brown 2014, Miller 2015, Pena 2016). Based on above information, this variant is considered likely pathogenic. References: Brown A et al. Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab. 2014 Dec;113(4):278-82. PMID: 25456746. Hesse J et al. The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). J Inherit Metab Dis. 2018 Nov;41(6):1169-1178. PMID: 30194637. Isackson P et al. Novel mutations in the gene encoding very long-chain acyl-CoA dehydrogenase identified in patients with partial carnitine palmitoyltransferase II deficiency. Muscle Nerve. 2013 Feb;47(2):224-9. PMID: 23169530. 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. 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. Spiekerkoetter U et al. Lethal Undiagnosed Very Long-Chain Acyl-CoA Dehydrogenase Deficiency with Mild C14-Acylcarnitine Abnormalities on Newborn Screening. JIMD Rep. 2012;6:113-5. PMID: 23430948.
Myriad Genetics, Inc.	RCV000527513	SCV002060066	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-10-01	criteria provided, single submitter	clinical testing	NM_000018.3(ACADVL):c.829_831delGAG(E277del) is an in-frame deletion classified as likely pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. E277del has been observed in cases with relevant disease (PMID: 27209629, 30194637, 32518924, 26385305, 23430948). Functional assessments of this variant are not available in the literature. E277del has been observed in population frequency databases (gnomAD: NFE 0.03%). In summary, NM_000018.3(ACADVL):c.829_831delGAG(E277del) is an in-frame deletion variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genetics and Molecular Pathology, SA Pathology	RCV000527513	SCV002556412	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-07-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519571	SCV003703416	likely pathogenic	Inborn genetic diseases	2021-09-22	criteria provided, single submitter	clinical testing	The c.829_831delGAG (p.E277del) alteration, located in coding exon 9 of the ACADVL gene, results from an in-frame GAG deletion at nucleotide positions 829 to 831. This results in the deletion of a glutamic acid residue at codon 277. Based on data from gnomAD, this allele has an overall frequency of 0.02% (47/282832) total alleles studied. The highest observed frequency was 0.04% (3/7226) of Other alleles. This alteration has been detected as compound heterozygous in multiple individuals diagnosed with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Spiekerkoetter, 2012; Pena, 2016; Hesse, 2018). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000527513	SCV004041107	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398921	SCV004103753	likely pathogenic	ACADVL-related disorder	2023-05-22	criteria provided, single submitter	clinical testing	The ACADVL c.829_831delGAG variant is predicted to result in an in-frame deletion (p.Glu277del). This variant was previously reported to be associated with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) and was observed in the compound heterozygous state in multiple patients (e.g., Spiekerkoetter et al. 2012. PubMed ID: 23430948; Yavarna et al. 2015. PubMed ID: 26077850; Pena et al. 2016. PubMed ID: 27209629; Knottnerus et al. 2020. PubMed ID: 32061778). Additionally, a similar variant involving an adjacent amino acid (c.833_835del; p.Lys278del) has also been observed in patients with VLCADD (Andresen et al. 1999. PubMed ID: 9973285; referred to as del830_32, delK238). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7125569-AAGG-A). Based on the collective evidence, the ACADVL c.829_831del variant is classified as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000527513	SCV004808027	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000527513	SCV004847520	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-06-30	criteria provided, single submitter	clinical testing	The p.Glu277del variant in ACADVL (also referred to as c.829_831delGAG in the literature) has been reported in six individuals with biochemical features of very long-chain acyl-CoA dehydrogenase deficiency including five compound heterozygotes (Pena 2016 PMID: 27209629, Adhikari 2020 PMID: 32778825, Knottnerus 2020 PMID: 32061778, Spiekerkoetter 2012 PMID: 23430948, Hesse 2018 PMID: 30194637). It has also been identified in 0.041% (28/68022) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 203589). This variant is a deletion of one amino acid at position 277 and is not predicted to alter the protein reading-frame. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Knottnerus 2020 PMID: 32061778, Spiekerkoetter 2012 PMID: 23430948); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive very long-chain acyl-CoA dehydrogenase deficiency. ACMG/AMP criteria applied with specifications by the ACADVL VCEP Expert Panel: PM3_Strong, PP4_Moderate, PM2_Supporting, PM4_Supporting, PP3, PS3_Moderate.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000527513	SCV001132831	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-01-29	flagged submission	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000527513	SCV001365200	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	flagged submission	clinical testing	The NM_000018.3:c.829_831delGAG (NP_000009.1:p.Glu277del) [GRCH38: NC_000017.11:g.7222253_7222255del] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported.This variant dose not meet any evidence codes reported in the ACMG guidelines.