rs1057516686
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_SupportingPVS1PP4
This summary comes from the ClinGen Evidence Repository: The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 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). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID:9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1,PM2_supporting,PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041866/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 splice_donor, splice_region, synonymous, intron
Scores
Clinical Significance
Conservation
Publications
- very long chain acyl-CoA dehydrogenase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000018.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ACADVL | NM_000018.4 | MANE Select | c.1077_1077+1delGGinsCAC | p.Ala359_Val360ins??? | splice_donor splice_region synonymous intron | N/A | NP_000009.1 | ||
| ACADVL | NM_001270447.2 | c.1146_1146+1delGGinsCAC | p.Ala382_Val383ins??? | splice_donor splice_region synonymous intron | N/A | NP_001257376.1 | |||
| ACADVL | NM_001033859.3 | c.1011_1011+1delGGinsCAC | p.Ala337_Val338ins??? | splice_donor splice_region synonymous intron | N/A | NP_001029031.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ACADVL | ENST00000356839.10 | TSL:1 MANE Select | c.1077_1077+1delGGinsCAC | p.Ala359_Val360ins??? | splice_donor splice_region synonymous intron | N/A | ENSP00000349297.5 | ||
| ACADVL | ENST00000350303.9 | TSL:1 | c.1011_1011+1delGGinsCAC | p.Ala337_Val338ins??? | splice_donor splice_region synonymous intron | N/A | ENSP00000344152.5 | ||
| ACADVL | ENST00000322910.9 | TSL:2 | n.*1032_*1032+1delGGinsCAC | splice_region non_coding_transcript_exon | Exon 9 of 19 | ENSP00000325395.5 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6
This variant results in the deletion of part of exon 10 (c.1077_1077+1delinsCAC) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Variant summary: ACADVL c.1077_1077+1delinsCAC 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: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244794 control chromosomes (gnomAD). The variant, c.1077_1077+1delinsCAC, has been reported in the literature in one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in whom no second allele was reported so the exact genotype could not be inferred (Andresen_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 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). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID: 9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1,PM2_supporting,PP4).
The NM_000018.3:c.1077_1077+1delinsCAC (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222865_7222866delinsCAC] 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
ACADVL-related disorder Pathogenic:1
The ACADVL c.1077_1077+1delinsCAC variant is predicted to result in an in-frame deletion and insertion. This change is predicted to abolish the canonical splice donor site. This variant was reported in an individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al. 1999. PubMed ID: 9973285; Intron 10 GG>CAC). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Canonical-splice altering variants in ACADVL are expected to be pathogenic, including several others reported at this same splice junction. This variant is interpreted as likely pathogenic.
not provided Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at