rs753108198
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000018.4(ACADVL):c.887_888del(p.Pro296ArgfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000229 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
ACADVL
NM_000018.4 frameshift
NM_000018.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.58
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-7222674-CCT-C is Pathogenic according to our data. Variant chr17-7222674-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189008.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7222674-CCT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.887_888del | p.Pro296ArgfsTer17 | frameshift_variant | 10/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.887_888del | p.Pro296ArgfsTer17 | frameshift_variant | 10/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152106Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
4
AN:
152106
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250254Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135372
GnomAD3 exomes
AF:
AC:
2
AN:
250254
Hom.:
AF XY:
AC XY:
0
AN XY:
135372
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461432Hom.: 0 AF XY: 0.0000234 AC XY: 17AN XY: 726962
GnomAD4 exome
AF:
AC:
33
AN:
1461432
Hom.:
AF XY:
AC XY:
17
AN XY:
726962
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74418
GnomAD4 genome
?
AF:
AC:
4
AN:
152224
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74418
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
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:10
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.887_888delCT (NP_000009.1:p.Pro296ArgfsTer17) [GRCH38: NC_000017.11:g.7222675_7222676delCT] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | ACADVL NM_000018.3 exon 10 p.Pro296Argfs*17 (c.887_888del): This variant has been reported in the literature in the homozygous or compound heterozygous state in multiple individuals with features of VLCAD deficiency (Schiff 2013 PMID:23480858, Hesse 2018 PMID:30194637, Wang 2019 PMID:31620161). Additionally, enzyme studies on fibroblast samples from two patients showed no detectible residual enzyme activity (Mathur 1999 PMID:10077518, Schiff 2013 PMID:23480858). This variant is present in 0.002% (1/34482) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-7125993-CCT-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:189008). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 17 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Andresen 1999 PMID:9973285). In summary, this variant is classified as pathogenic based on the data above. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2019 | Variant summary: ACADVL c.887_888delCT (p.Pro296ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250254 control chromosomes (gnomAD). c.887_888delCT has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Hesse_2018, Mathur_1999, Schiff_2013, Wang_2019). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 29, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 17, 2020 | The p.Pro296ArgfsX17 variant in ACADVL has been reported in several individuals with very long chain acyl-CoA dehydrogenase deficiency (VLCADD), including at least 1 homozygous and 3 compound heterozygous individuals (Hesse 2018 PMID 30194637; Roe 2002 PMID:12122118; Wang 2019 PMID:31620161; Mathur 1999 PMID:10077518; Miller 2015 PMID:26385305; Schiff 2013 PMID:23480858). It has also been identified in 2/250254 of the total chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 296 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ACADVL gene is an established disease mechanism in autosomal recessive VLCADD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VLCADD. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Strong. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 10, 2023 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Jun 13, 2023 | The c.887_888del (p.Pro296ArgfsTer17) variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 10/20 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 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has also been reported in patients with phenotypes suggestive of a fatty acid oxidation defect (PMIDs: 10077518, 32778825). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1+PM2_supporting). - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 08, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 10, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change creates a premature translational stop signal (p.Pro296Argfs*17) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs753108198, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23480858, 30194637). ClinVar contains an entry for this variant (Variation ID: 189008). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2014 | The c.887_888delCT mutation has been reported previously in association with VLCAD deficiency (Mathur et al., 1999). The deletion causes a frameshift starting with codon Proline 296, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Pro296ArgfsX17. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in ACADVL panel(s). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at