rs200788251

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PM2_SupportingPS3_SupportingPP4_ModeratePM3

This summary comes from the ClinGen Evidence Repository: The c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID:14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID:14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337873/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

10

6

3

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 8.34

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS3

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/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.865G>A	p.Gly289Arg	missense_variant	9/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.865G>A	p.Gly289Arg	missense_variant	9/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

20

AN:

152136

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000107

AC:

27

AN:

251232

Hom.:

0

AF XY:

0.000125

AC XY:

17

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461744

Hom.:

0

Cov.:

32

AF XY:

0.000191

AC XY:

139

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000131

AC:

20

AN:

152254

Hom.:

0

Cov.:

32

AF XY:

0.0000806

AC XY:

6

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000373

Hom.:

0

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.000349

AC:

3

ExAC

AF:

0.0000906

AC:

11

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2023	Variant summary: ACADVL c.865G>A (p.Gly289Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 0.00011 in 251232 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00011 vs 0.0029), allowing no conclusion about variant significance. c.865G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, PMID: 14517516, 27209629, 31031081, 30194637). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 23480858). The most pronounced variant effect results in 15% of normal VLCAD activity in-vitro. Seven 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 289 of the ACADVL protein (p.Gly289Arg). This variant is present in population databases (rs200788251, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 14517516, 23480858, 27209629, 27246109). ClinVar contains an entry for this variant (Variation ID: 370981). 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) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 23480858). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 27, 2016	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Jun 27, 2023	The c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID: 14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID: 14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 22, 2018	Across a selection of the available literature, the ACADVL c.865G>A (p.Gly289Arg) variant has been reported in a compound heterozygous state in at least six individuals identified as having VLCAD deficiency through newborn screening (Spiekerkoetter et al. 2003; Schiff et al. 2013; Waisbren et al. 2013; Pena et al. 2016; Evans et al. 2016). Several of these individuals were described as asymptomatic, however, speech/language and motor delays, autistic spectrum behavior and relative weakness in the fine motor area were reported in two individuals after at least two years of follow-up (Waisbren et al. 2013). Analysis of 693 unrelated individuals with a positive newborn screening result for VLCAD deficiency, identified the p.Gly289Arg variant on six alleles from affected individuals (Miller et al. (2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Fibroblasts from one individual who was compound heterozygous for the p.Gly289Arg variant, exhibited no detectable enzyme activity and absent protein expression based on Western blot analysis. In vitro expression analyses in E. coli showed that the p.Gly289Arg variant displayed 15% of wildtype activity and reduced protein expression (Schiff et al. 2013). Based on the collective evidence, the p.Gly289Arg variant is classified as pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2019	The ACADVL c.865G>A; p.Gly289Arg variant (rs200788251), also known as p.Gly249Arg, is reported in the literature in the compound heterozygous state in individuals affected with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Evans 2016, Pena 2016, Schiff 2013, Spiekerkoetter 2003). This variant is also reported in ClinVar (Variation ID: 370981). It is found in the general population with an overall allele frequency of 0.01% (32/282608 alleles) in the Genome Aggregation Database. The glycine at codon 289 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, in vitro functional analyses demonstrate a significant reduction in protein activity compared to wildtype (Schiff 2013). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. 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. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 109(1):21-7. Spiekerkoetter U et al. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2003 143(3):335-42. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.865G>A (NP_000009.1:p.Gly289Arg) [GRCH38: NC_000017.11:g.7222289G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516; 27209629 . This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 02, 2023	PM1, PM2, PM3, PP2, PP3, PP5 - The variant has been reported in ClinVar by other laboratories (Variation ID 370981). Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It was detected in trans with another pathogenic variant. It has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (PMID: 31031081, 30194637). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2024

Published functional studies demonstrate a damaging effect: expression of G289R in E. coli found that it is associated with approximately 15% residual enzyme activity (PMID: 23480858); 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: 23798014, 27209629, 25087612, 25242572, 14517516, 20547398, 30194637, 21228398, 31031081, 31980526, 33658040, 32778825, 31589614, 23480858) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.21

D

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.74

D

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Benign

1.5

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

T

PROVEAN

Pathogenic

-7.0

D;.;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.90

MutPred

0.81

.;Gain of solvent accessibility (P = 0.0306);.;

MVP

0.99

MPC

0.80

ClinPred

0.73

D

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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: rs200788251; hg19: chr17-7125608;