chr17-7223816-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000018.4(ACADVL):​c.1273G>A​(p.Ala425Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

4
8
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:4

Conservation

PhyloP100: 6.58
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-7223816-G-A is Pathogenic according to our data. Variant chr17-7223816-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92273.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.1273G>A p.Ala425Thr missense_variant Exon 13 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.1273G>A p.Ala425Thr missense_variant Exon 13 of 20 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251466
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461854
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000941
AC XY:
7
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.000314
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000850
Hom.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4Uncertain:2
Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ACADVL c.1273G>A; p.Ala425Thr variant (rs138834083) is reported in the literature in the heterozygous or compound heterozygous state with a second pathogenic variant in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (Chien 2013, Miller 2015, Pena 2016). This variant is reported in ClinVar (Variation ID: 92273), and is found in the African population with an allele frequency of 0.064% (16/24,966 alleles) in the Genome Aggregation Database. The alanine at codon 425 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.722). Based on available information, this variant is considered to be likely pathogenic. References: Chien YH et al. Fatty Acid oxidation disorders in a chinese population in taiwan. JIMD Rep. 2013;11:165-72. PMID: 23700290. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PMID: 27209629. -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 425 of the ACADVL protein (p.Ala425Thr). This variant is present in population databases (rs138834083, gnomAD 0.07%). This missense change has been observed in individuals with very long chain acyl-CoA dehydrogenase deficiency (PMID: 23700290, 27209629; internal data). ClinVar contains an entry for this variant (Variation ID: 92273). Invitae Evidence 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 not expected to disrupt ACADVL protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mar 04, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2019
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NM_000018.3:c.1273G>A (NP_000009.1:p.Ala425Thr) [GRCH38: NC_000017.11:g.7223816G>A] 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: PP3 -

Jun 19, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:2Uncertain:1
Dec 16, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in multiple individuals with a positive newborn screening result for VLCAD deficiency in whom a second variant in the ACADVL gene was not identified (PMID: 26385305); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23700290, 26385305, 20480395, 27209629) -

Aug 24, 2018
Eurofins Ntd Llc (ga)
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 07, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PP4_moderate, PM2, PS4_moderate -

not specified Uncertain:1
Jan 25, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ACADVL c.1273G>A (p.Ala425Thr) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251466 control chromosomes. c.1273G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, PMID: 23700290, 31794763, 26385305, 27209629). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=4; P/LP, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Uncertain
0.073
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
27
DANN
Benign
0.94
DEOGEN2
Uncertain
0.72
.;D;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.57
D
MetaRNN
Uncertain
0.70
D;D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Benign
1.3
.;L;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-2.3
N;.;N
REVEL
Pathogenic
0.72
Sift
Benign
0.045
D;.;D
Sift4G
Benign
0.080
T;T;T
Polyphen
1.0, 0.92
.;D;P
Vest4
0.83
MVP
0.97
MPC
0.75
ClinPred
0.17
T
GERP RS
5.8
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
3.8
Varity_R
0.80
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

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: rs138834083; hg19: chr17-7127135; API