Submissions for variant NM_000018.4(ACADVL):c.753-2A>C

gnomAD frequency: 0.00001  dbSNP: rs398123092

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000180449	SCV002769743	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-05-09	reviewed by expert panel	curation	The c.753-2A>C variant in ACADVL occurs within the canonical splice acceptor site (+/- 1,2) of intron 8. It is predicted to cause skipping of biologically-relevant-exon 9/20, resulting in an in frame deletion (removes amino acids 252-293) that is predicted to escape nonsense mediated decay (PVS1_moderate). This variant has been identified by positive newborn screen in several individuals and in individuals presenting with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27246109, 26385305, 21378393, 17999356, 16488171, 10738914, 10077518, 9973285). This variant is reported in two individuals with a beta-oxidation flux less than 20% of normal which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. (PP4_Moderate, PMID: 21378393, 17999356, 20060901). At least three individuals were compound heterozygous for the variant and a distinct pathogenic or likely pathogenic variant, not confirmed in trans (PM3; PMID: 27246109, 16488171, 20060901, 21378393, 17999356). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM2_Supporting, PM3, PP4_Moderate (VCEP specifications v2.0, approved November 9, 2021).
Eurofins Ntd Llc (ga)	RCV000077923	SCV000232891	pathogenic	not provided	2013-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000077923	SCV000616632	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing	The c.753-2 A>C splice site variant in the ACADVL gene has been previously reported in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al., 1999; Evans et al., 2016). The c.753-2 A>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant destroys the canonical splice acceptor site in intron 8, and is expected to cause abnormal gene splicing.
Invitae	RCV000180449	SCV000654967	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs398123092, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with VLCAD deficiency (PMID: 10077518, 10738914, 17999356, 27246109). ClinVar contains an entry for this variant (Variation ID: 92290). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000180449	SCV001158614	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-06-15	criteria provided, single submitter	clinical testing	The ACADVL c.753-2A>C variant (rs398123092) has been described in individuals with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen 1999, Boneh 2006, Mathur 1999). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 92290) and is observed in the general population at a low overall frequency of 0.0007% (2/277214 alleles) in the Genome Aggregation Database. This is an intronic variant, the nucleotide at this position is highly conserved and computational algorithms (Alamut v.2.10) predict this variant will alter mRNA splicing by disrupting the acceptor splice site in intron 8. Based on the above information, this variant is considered pathogenic. References: Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Boneh A et al. VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. Mol Genet Metab. 2006 Jun;88(2):166-70. Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. 1999 Mar 16;99(10):1337-43.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000180449	SCV001364902	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.753-2A>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222175A>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180449	SCV001448470	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-11-25	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.753-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Experimental evidence demonstrated this variant affects the mRNA product (Andersen_1999). The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.753-2A>C has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Andresen_1999, Pons_2000, Boneh_2006, Bastin_2011). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000180449	SCV002060168	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-11-08	criteria provided, single submitter	clinical testing	NM_000018.3(ACADVL):c.753-2A>C is a canonical splice variant classified as pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. c.753-2A>C has been observed in cases with relevant disease (PMID: 10738914, 17999356). Functional assessments of this variant are not available in the literature. c.753-2A>C has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_000018.3(ACADVL):c.753-2A>C is a canonical splice 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.
Baylor Genetics	RCV000180449	SCV004215180	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-07-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000180449	SCV002088763	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-01-27	no assertion criteria provided	clinical testing