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

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 splice_acceptor, intron

Scores

3
3
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 7.71
Variant links:
Genes affected
ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACADVLNM_000018.4 linkc.753-2A>C splice_acceptor_variant, intron_variant ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.753-2A>C splice_acceptor_variant, intron_variant 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251484
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.0000220
AC XY:
16
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000252
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000688
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:12
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 15, 2022The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 25, 2020Variant 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 submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineNov 01, 2019The 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 submitterclinical testingBaylor GeneticsMar 28, 2024- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterApr 23, 2024PVS1, PS3_Moderate, PM3 -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024This 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 panelcurationClinGen ACADVL Variant Curation Expert Panel, ClinGenMay 09, 2023The 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 submitterclinical testingMyriad Genetics, Inc.Nov 08, 2021NM_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 providedclinical testingNatera, Inc.Jan 27, 2021- -
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 17, 2025Canonical 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 submitterclinical testingEurofins Ntd Llc (ga)Jul 17, 2013- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024ACADVL: PM3:Very Strong, PVS1:Strong, PM2, PP4:Moderate, PS1:Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Uncertain
0.97
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.52
Position offset: -48
DS_AL_spliceai
0.97
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs398123092; hg19: chr17-7125494; API