rs750043368
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000018.4(ACADVL):c.227G>A(p.Gly76Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
ACADVL
NM_000018.4 missense
NM_000018.4 missense
Scores
4
5
8
Clinical Significance
Conservation
PhyloP100: 2.81
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000018.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.822
PP5
?
Variant 17-7220626-G-A is Pathogenic according to our data. Variant chr17-7220626-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554006.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.227G>A | p.Gly76Glu | missense_variant | 4/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.227G>A | p.Gly76Glu | missense_variant | 4/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251474Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD3 exomes
AF:
AC:
2
AN:
251474
Hom.:
AF XY:
AC XY:
2
AN XY:
135920
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: 0.00000889 AC: 13AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727246
GnomAD4 exome
AF:
AC:
13
AN:
1461890
Hom.:
Cov.:
33
AF XY:
AC XY:
8
AN XY:
727246
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 ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ExAC
?
AF:
AC:
2
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 21, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2017 | The ACADVL c.227G>A (p.Gly76Glu) variant has been reported in a compound heterozygous state with another missense variant in an individual who initially presented with elevated C14:1-carnitine levels (Schymik et al. 2006). Of note, this variant is reported as c.227G>A, but described as p.Gly36Gln in the study. This patient's mother was found to be heterozygous for the c.227G>A (p.Gly36Gln) variant and the father was heterozygous for the other variant. Control data are not available for the p.Gly76Glu variant which is reported at a frequency of 0.000121 in the South Asian population from the Exome Aggregation Consortium; however this is based on two alleles so the variant is presumed to be rare. VLCAD enzyme activity was measured in lymphocyte homogenates from the patient who was compound heterozygous for the c.227G>A (p.Gly36Gln) variant and no residual enzyme activity was detected. The evidence for this variant is limited. Therefore, the p.Gly76Glu variant is considered to be of unknown significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 76 of the ACADVL protein (p.Gly76Glu). This variant is present in population databases (rs750043368, gnomAD 0.006%). This missense change has been observed in individual(s) with very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 16860141, 30194637). This variant is also known as G36Q. ClinVar contains an entry for this variant (Variation ID: 554006). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADVL protein function. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The missense c.227G>A(p.Gly76Glu) variant in ACADVL gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with very-long-chain acyl-CoA dehydrogenase deficiency (Hesse J et al., 2018). This variant is reported with the allele frequency of 0.0008% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic. The amino acid Gly at position 76 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly76Glu in ACADVL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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) indicates that this missense variant is expected to disrupt ACADVL protein function. For these reasons, this variant has been classified as Likely Pathogenic. . - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 17, 2021 | Variant summary: ACADVL c.227G>A (p.Gly76Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.227G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Schymik_2006). This report does not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2022 | The c.227G>A (p.G76E) alteration is located in exon 4 (coding exon 4) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 227, causing the glycine (G) at amino acid position 76 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D;T;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.
REVEL
Pathogenic
Sift
Benign
T;.;.;T;.
Sift4G
Benign
T;T;T;T;D
Polyphen
0.99, 0.14
.;D;.;B;.
Vest4
MutPred
0.77
.;Gain of disorder (P = 0.0576);Gain of disorder (P = 0.0576);.;Gain of disorder (P = 0.0576);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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