rs779901247

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000018.4(ACADVL):ā€‹c.1504C>Gā€‹(p.Leu502Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L502P) has been classified as Likely pathogenic.

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 0.916
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.1504C>G p.Leu502Val missense_variant Exon 15 of 20 ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.1504C>G p.Leu502Val missense_variant Exon 15 of 20 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461734
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineNov 01, 2019The NM_000018.3:c.1504C>G (NP_000009.1:p.Leu502Val) [GRCH38: NC_000017.11:g.7224215C>G] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM5, PP3 -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 16, 2021NM_000018.3(ACADVL):c.1504C>G(L502V) is a missense variant classified as a variant of uncertain significance in the context of very long chain acyl-CoA dehydrogenase deficiency. L502V has been observed in cases with relevant disease (PMID: 26385305, 27209629, 23867825, 23418865). Functional assessments of this variant are not available in the literature. L502V has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1504C>G(L502V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 31, 2022This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 502 of the ACADVL protein (p.Leu502Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23867825, 27209629, 31031081). ClinVar contains an entry for this variant (Variation ID: 203586). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Pathogenic:1
Likely pathogenic, flagged submissionclinical testingEurofins Ntd Llc (ga)Jul 06, 2015- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 21, 2025Variant summary: ACADVL c.1504C>G (p.Leu502Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1504C>G has been reported in the literature in individuals diagnosed with Very Long Chain Acyl-CoA Dehydrogenase Deficiency by newborn screen with unclear clinical diagnoses (Erlingsson_2013, Pena_2016, Rovelli_2019). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 23867825, 27209629, 31031081). ClinVar contains an entry for this variant (Variation ID: 203586). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 09, 2023The c.1504C>G (p.L502V) alteration is located in exon 15 (coding exon 15) of the ACADVL gene. This alteration results from a C to G substitution at nucleotide position 1504, causing the leucine (L) at amino acid position 502 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
0.0080
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
21
DANN
Benign
0.82
DEOGEN2
Benign
0.19
.;T;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.86
D;D;D
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.1
.;L;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.83
N;.;N
REVEL
Benign
0.14
Sift
Benign
0.19
T;.;T
Sift4G
Benign
0.24
T;T;T
Polyphen
0.17, 0.0090
.;B;B
Vest4
0.39
MutPred
0.39
.;Gain of MoRF binding (P = 0.0786);.;
MVP
0.67
MPC
0.20
ClinPred
0.46
T
GERP RS
0.30
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.060
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.57
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.57
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779901247; hg19: chr17-7127534; API