NM_000018.4:c.1322G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3_StrongPM2PP4_ModeratePM1PP3

This summary comes from the ClinGen Evidence Repository: The c.1322G>A (p.Gly441Asp) variant in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 441. At least two individuals with this variant displayed VLCAD enzyme activity <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID:25834949). The variant has been described in the homozygous state in at least 4 affected individuals, confirmed in trans to a pathogenic variant in at least one individual, and in at least one individual with a distinct pathogenic variant without determination of phase of the variants (PM3_Strong; PMIDs: 1648817, 17999356, 24305961, 30194637, 32061778). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion. This variant occurs adjacent to the FAD binding pocket and is located on a loop that contributes to dimer formation (PM1; PMID:20060901). The computational predictor REVEL gives a score of 0.982, 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 pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA220193/MONDO:0008723/021

Frequency

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

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16

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]

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4 link	c.1322G>A	p.Gly441Asp	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.1322G>A	p.Gly441Asp	missense_variant	Exon 13 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251362

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727196

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:

0.0000342

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000919

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:12

Feb 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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.1322G>A (NP_000009.1:p.Gly441Asp) [GRCH38: NC_000017.11:g.7223865G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17999356. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 14, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1322G>A (p.Gly441Asp) variant in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 441. At least two individuals with this variant displayed VLCAD enzyme activity <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 25834949). The variant has been described in the homozygous state in at least 4 affected individuals, confirmed in trans to a pathogenic variant in at least one individual, and in at least one individual with a distinct pathogenic variant without determination of phase of the variants (PM3_Strong; PMIDs: 1648817, 17999356, 24305961, 30194637, 32061778). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion. This variant occurs adjacent to the FAD binding pocket and is located on a loop that contributes to dimer formation (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.982, 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 pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) -

Sep 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1322G>A; p.Gly441Asp variant (rs2309689) is reported in the literature in several compound heterozygous individuals and a homozygous individual affected with VLCAD deficiency (Andresen 1996, Diekman 2015, Gobin-Limballe 2010, Hesse 2018). This variant is also reported in ClinVar (Variation ID: 21016) and is found in the non-Finnish European population with an allele frequency of 0.006% (7/113,746 alleles) in the Genome Aggregation Database (v2.1.1). In vitro functional analyses of patient fibroblasts demonstrate <20% of wild type VLCAD enzyme activity (Diekman 2015, Gobin-Limballe 2010, Hesse 2018). Computational analyses predict that this variant is deleterious (REVEL: 0.982). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996 Apr;5(4):461-72. PMID: 8845838. Diekman EF et al. Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency. Genet Med. 2015 Dec;17(12):989-94. PMID: 25834949. 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. Hesse J et al. The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). J Inherit Metab Dis. 2018 Nov;41(6):1169-1178. PMID: 30194637. -

May 04, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 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 441 of the ACADVL protein (p.Gly441Asp). This variant is present in population databases (rs2309689, gnomAD 0.005%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 8845838, 16443431, 17999356, 24305961). ClinVar contains an entry for this variant (Variation ID: 21016). 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%. For these reasons, this variant has been classified as Pathogenic. -

Jun 04, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADVL c.1322G>A (p.Gly441Asp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251362 control chromosomes (gnomAD). c.1322G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Diekman_2015, Miller_2015, Gobin-Limballe_2010, Andresen_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated fibroblast cells derived from VLCAD patients carrying p.Gly441Asp to have considerably reduced enzyme activity and long-chain fatty acid-oxidation flux compared to controls (Diekman_2015, Gobin-Limballe_2010, Andresen_1996). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 03, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1 -

not provided

Pathogenic:4

May 03, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PM3, PP4 -

Nov 13, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8845838, 25525159, 16288870, 16443431, 31031081, 20060901, 17999356, 23867825, 16488171, 9546340, 26453363, 23757202, 27246109, 11158518, 20301763, 21378393) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

.;H;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.5

D;.;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.91

MVP

0.99

MPC

0.88

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

1.0

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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