rs751995154

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPP4_ModeratePM1PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1376G>A variant is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 459 (p.Arg459Gln). This variant has been reported in at least 11 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, with two individuals displaying both reduced VLCAD activity and increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID:30194637; PMID:21429517; PMID:19327992). In these individuals, the variant was detected three times in the homozygous state plus 1 confirmed in-trans and 5 not confirmed in-trans with the pathogenic variant c.848T>C (PM3_strong; PMID:30194637; PMID:21429517). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004646 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 (PM2_Supporting). The variant is located in a well-studied dimerization domain which is critical for the protein's dimer interaction (PM1; PMID:14517516). The computational predictor REVEL gives a score of 0.864, 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; PM1; PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA312275/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 1 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 8.54

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 10 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.1376G>A	p.Arg459Gln	missense_variant	Exon 14 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.1376G>A	p.Arg459Gln	missense_variant	Exon 14 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251410

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135898

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727232

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000598

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:13

Dec 18, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PM5_STR,PM2_SUP,PP3 -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: 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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.1376G>A (NP_000009.1:p.Arg459Gln) [GRCH38: NC_000017.11:g.7224011G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 14517516. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Mar 10, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1376G>A variant is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 459 (p.Arg459Gln). This variant has been reported in at least 11 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, with two individuals displaying both reduced VLCAD activity and increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 30194637; PMID: 21429517; PMID: 19327992). In these individuals, the variant was detected three times in the homozygous state plus 1 confirmed in-trans and 5 not confirmed in-trans with the pathogenic variant c.848T>C (PM3_strong; PMID: 30194637; PMID: 21429517). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004646 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 (PM2_Supporting). The variant is located in a well-studied dimerization domain which is critical for the protein's dimer interaction (PM1; PMID: 14517516). The computational predictor REVEL gives a score of 0.864, 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; PM1; PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). -

Apr 02, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3_VeryStrong+PP3+PP4 -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 459 of the ACADVL protein (p.Arg459Gln). This variant is present in population databases (rs751995154, gnomAD 0.005%). This missense change has been observed in individual(s) with VLCAD deficiency, several of them being clinically asymptomatic (PMID: 14517516, 19327992, 21429517, 23798014, 30194637). This variant is also known as p.Arg419Gln. ClinVar contains an entry for this variant (Variation ID: 203585). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADVL protein function. For these reasons, this variant has been classified as Pathogenic. -

Oct 12, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant in exon 14 of the ACADVL gene that results in the amino acid substitution of Glutamine for Arginine at codon 459 (p.Arg459Gln) was detected. The observed variant has previously been reported in patients affected with VLCAD deficiency and functional characterization of patient fibroblasts indicates significant reduction in VLCAD enzymatic activity [PMID: 19327992]. The variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.003%, 0.002% and 0.003% in the gnomAD (v3.1), gnomdAD (v2), and topmed databases respectively. The in-silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Sep 09, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1376G>A; p.Arg459Gln variant (rs751995154), also known as p.Arg419Gln in traditional nomenclature, is reported in the literature in individuals with Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency (Laforet 2009, McGoey 2011, Miller 2015, Spiekerkoetter 2003, Waisbren 2013) and has been found in trans to other pathogenic variants (McGoey 2011, Spiekerkoetter 2003). Functional characterization of patient fibroblasts indicates significant reduction in VLCAD enzymatic activity (Laforet 2009). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 203585), and it is found on only eight chromosomes (8/282800 alleles) in the Genome Aggregation Database. The arginine at residue 459 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.864). Additional, another variant at the same codon (p.Arg459Trp) has been reported in individuals with VLCAD deficiency and is considered pathogenic (Andresen 1999, Miller 2015). Based on the above information, the p.Arg459Gln variant is considered to be pathogenic. References: Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. PMID: 9973285. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009; 19(5):324-9. PMID: 19327992 McGoey R et al. Positive newborn screen in a normal infant of a mother with asymptomatic very long-chain Acyl-CoA dehydrogenase deficiency. J Pediatr. 2011; 158(6):1031-2. PMID: 21429517. 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 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. PMID: 14517516 Waisbren S et al. Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev. 2013; 17(3):260-8. PMID: 23798014. -

Jun 06, 2024

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.1376G>A (p.Arg459Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Three 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 251410 control chromosomes, predominantly at a frequency of 4.4e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.1376G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Bozovic_2021, Capalbo_2019, Lin_2020,2023, Savarese_2014, Spiekerkoetter_2003). These data indicate that the variant is likely to be associated with disease. 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: 34106991, 31589614, 30904546, 32710939, 25214167, 14517516). ClinVar contains an entry for this variant (Variation ID: 203585). Based on the evidence outlined above, the variant was classified as pathogenic. -

ACADVL-related disorder

Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADVL c.1376G>A variant is predicted to result in the amino acid substitution p.Arg459Gln. This variant has been reported in multiple individuals with very long chain acyl-CoA dehydrogenase deficiency (VLCADD), the majority of which have been identified via newborn screening (Spiekerkoetter et al. 2003. PubMed ID: 14517516; McGoey and Marble. 2011. PubMed ID: 21429517; Miller et al. 2015. PubMed ID: 26385305). Only a few patients with the c.1376G>A variant have been reported to be clinically symptomatic (Laforêt et al. 2009. PubMed ID: 19327992; Waisbren et al. 2013. PubMed ID: 23798014; Savarese et al. 2014. PubMed ID: 25214167). Available splicing prediction algorithms (SpliceAI; Alamut Visual v1.6.1) indicate that this variant may create a novel splice acceptor site within ACADVL exon 14 (based on transcript NM_000018.3). However, it should be noted that such predictions are not equivalent to functional evidence. This variant is reported in 0.0046% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been classified as pathogenic by the ClinGen ACADVL Variant Curation Expert Panel and most submitters in clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/203585/). Based on collective evidence, this variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 24, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1376G>A (p.R459Q) alteration is located in exon 14 (coding exon 14) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 1376, causing the arginine (R) at amino acid position 459 to be replaced by a glutamine (Q). This alteration has been reported in the compound heterozygous and homozygous states in multiple individuals diagnosed with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Hesse, 2018; Laforêt, 2009; McGoey, 2011; Spiekerkoetter, 2003; Waisbren, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Dec 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21429517, 25214167, 32710939, 14517516, 26385305, 23798014, 19327992, 31589614, 34106991) -

Myopathy;C0035410:Rhabdomyolysis

Pathogenic:1

Jan 23, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Benign

0.83

DEOGEN2

Pathogenic

0.91

.;D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

D;.;D

REVEL

Pathogenic

0.86

Sift

Benign

0.094

T;.;T

Sift4G

Benign

0.069

T;T;T

Polyphen

1.0, 0.99

.;D;D

Vest4

0.94

MutPred

0.95

.;Loss of MoRF binding (P = 0.0436);.;

MVP

0.98

MPC

0.82

ClinPred

0.66

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 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