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
Consequence
NM_000018.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249894Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135144
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1458880Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 725704
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 08, 2024 | This 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 submitter | clinical testing | Revvity Omics, Revvity | Sep 21, 2022 | - - |
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.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 submitter | clinical testing | Counsyl | Apr 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 27, 2025 | Variant 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 panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Jul 12, 2022 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2023 | Published 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at