chr17-7223859-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000018.4(ACADVL):c.1316G>A(p.Gly439Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,614,086 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 6.77

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]

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 17-7223859-G-A is Pathogenic according to our data. Variant chr17-7223859-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4 link	c.1316G>A	p.Gly439Asp	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
ACADVL	ENST00000356839.10 link	c.1316G>A	p.Gly439Asp	missense_variant	Exon 13 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251404

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727204

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:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:5

Nov 01, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.1316G>A (NP_000009.1:p.Gly439Asp) [GRCH38: NC_000017.11:g.7223859G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Mar 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1316G>A; p.Gly439Asp variant (rs533055438) is reported in the literature in the compound heterozygous state in individuals diagnosed with VLCAD deficiency (Gobin-Limballe 2010, Pena 2016, Schiff 2013). This variant is reported in ClinVar (Variation ID: 203582), and found in the general population with an allele frequency of 0.002% (6/277134 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.964), and functional analyses of the variant protein show no enzyme activity (Schiff 2013). Based on available information, this variant is considered pathogenic. References: Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. PMID: 20060901. 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. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. PMID: 23480858. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 439 of the ACADVL protein (p.Gly439Asp). This variant is present in population databases (rs533055438, gnomAD 0.005%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 17999356, 23480858; internal data). ClinVar contains an entry for this variant (Variation ID: 203582). 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 expected to disrupt ACADVL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 23480858). This variant disrupts the p.Gly439 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:1

Jan 31, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Expression of G439D in E. coli found no detectable enzyme activity compared to wild-type controls (PMID: 23480858); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30925787, 23169530, 27209629, 30194637, 31031081, 20060901, 23480858, 17999356) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

.;H;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.8

D;.;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.97

MVP

0.99

MPC

0.87

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over