chr17-7222866-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_SupportingPVS1

This summary comes from the ClinGen Evidence Repository: The c.1077+1G>A variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PMID:26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA287437693/MONDO:0008723/021

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 6.62
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 9 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.1077+1G>A splice_donor_variant, intron_variant Intron 10 of 19 ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.1077+1G>A splice_donor_variant, intron_variant Intron 10 of 19 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
249894
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135144
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1458880
Hom.:
0
Cov.:
32
AF XY:
0.00000551
AC XY:
4
AN XY:
725704
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:8
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 08, 2024This sequence change affects a donor splice site in intron 10 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 (rs140989450, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 25338548, 30194637). ClinVar contains an entry for this variant (Variation ID: 448981). 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, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 21, 2022- -
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineNov 01, 2019The NM_000018.3:c.1077+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222866G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylApr 17, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 11, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 27, 2025Variant summary: ACADVL c.1077+1G>A 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ACADVL function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249894 control chromosomes (gnomAD). c.1077+1G>A has been reported in the literature in individuals affected with very long chain acyl-CoA dehydrogenase deficiency. However, the information of the second variant has not been specified (example: Rouyer_2024, Miller_2015). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38015438, 26385305). ClinVar contains an entry for this variant (Variation ID: 448981). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panelcurationClinGen ACADVL Variant Curation Expert Panel, ClinGenJul 12, 2022The c.1077+1G>A variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PMID: 26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 27, 2023Published in an individual with an abnormal newborn screening result for VLCAD deficiency; a second variant was not identified (Miller et al. 2015); Canonical splice site variant predicted to result in a null allele 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: 34426522, 11590124, 26385305, 9973285, 25338548, 30194637) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.97
D
GERP RS
5.6
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
3.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.54
Position offset: 24
DS_DL_spliceai
0.98
Position offset: -1

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: rs140989450; hg19: chr17-7126185; API