rs398123092
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_ModeratePM2_SupportingPM3PVS1_Moderate
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220220/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727238
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 15, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 25, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 23, 2024 | PVS1, PS3_Moderate, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | 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. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | May 09, 2023 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 27, 2021 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2025 | Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 9973285, 21378393, 16488171, 17999356, 10738914, 10077518, 27246109) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 17, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ACADVL: PM3:Very Strong, PVS1:Strong, PM2, PP4:Moderate, PS1:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at