rs759775666
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong
The NM_000018.4(ACADVL):c.1468G>C(p.Ala490Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A490G) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
ACADVL
NM_000018.4 missense
NM_000018.4 missense
Scores
9
6
2
Clinical Significance
Conservation
PhyloP100: 4.20
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 Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-7224180-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2754607.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
?
Variant 17-7224179-G-C is Pathogenic according to our data. Variant chr17-7224179-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 474888.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1468G>C | p.Ala490Pro | missense_variant | 15/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1468G>C | p.Ala490Pro | missense_variant | 15/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251362Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461852Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727224
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 490 of the ACADVL protein (p.Ala490Pro). This variant is present in population databases (rs759775666, gnomAD 0.004%). This missense change has been observed in individual(s) with known or suggested very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 10077518, 14517516, 26453363). This variant is also known as A450P. ClinVar contains an entry for this variant (Variation ID: 474888). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 17374501). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Apr 11, 2023 | The c.1468G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 490 (p.Ala490Pro), also known as Ala450Pro when numbered from the mature protein. This variant has been detected in at least 5 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 2 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variant, presumed to be in trans (PM3_Supporting, PMID: 26453363, 30194637). This variant has been described in at least 3 unrelated individuals who displayed VLCAD enzyme activity <20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:26453363, 14517516, 30194637). The variant has been reported to segregate with VLCAD deficiency in 2 affected siblings from 1 family (PP1, PMID: 14517516). This variant resides within a region, amino acids 481-516, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PMID: 18227065, 20060901). A substrate specificity assay showed this variant displays abnormal substrate specificity; however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9839948). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: PM1, PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 13, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 09, 2023 | - - |
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.1468G>C (NP_000009.1:p.Ala490Pro) [GRCH38: NC_000017.11:g.7224179G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9839948; 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;D;D
Polyphen
0.98, 0.99
.;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at