rs118204016

Positions:

chr17-7223984-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3_StrongPM2_SupportingPP3PP4

This summary comes from the ClinGen Evidence Repository: The c.1349G>A (p.Arg450His) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 450. At least one individual with this variant displayed reduced VLCAD activity, which is specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMID:11158518). This variant has been confirmed in trans to at least one likely pathogenic variant, not confirmed in trans to distinct likely pathogenic variants, and has been identified in the homozygous state in 2 individuals (PM3_Strong, PMID:29519241, 15210884, 11158518, 9546340). The highest population minor allele frequency in gnomAD v2.0 is 0.00025 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, 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 likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA251910/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

ACADVL
ENST00000356839.10 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13U:1

Conservation

PhyloP100: 6.40

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 Likely_pathogenic. Variant got 7 ACMG points.

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.1349G>A	p.Arg450His	missense_variant	14/20	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.1349G>A	p.Arg450His	missense_variant	14/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152174

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:

0.000386

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:

0.0000239

AC:

AN:

251342

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:9Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ACADVL protein (p.Arg450His). This variant is present in population databases (rs118204016, gnomAD 0.03%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9546340, 11158518, 15210884, 24801231). This variant is also known as R410H. ClinVar contains an entry for this variant (Variation ID: 1634). 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: 11158518). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 09, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 14, 2022	The c.1349G>A (p.Arg450His) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 450. At least one individual with this variant displayed reduced VLCAD activity, which is specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 11158518). This variant has been confirmed in trans to at least one likely pathogenic variant, not confirmed in trans to distinct likely pathogenic variants, and has been identified in the homozygous state in 2 individuals (PM3_Strong, PMID: 29519241, 15210884, 11158518, 9546340). The highest population minor allele frequency in gnomAD v2.0 is 0.00025 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, 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 likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, PM3_Strong, PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 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.1349G>A (NP_000009.1:p.Arg450His) [GRCH38: NC_000017.11:g.7223984G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2024	The p.Arg473His variant in ACADVL has been reported in the homozygous state in at least 2 individuals and in the compound heterozygous state in at least 7 individuals with very long chain acyl-CoA dehydrogenase deficiency, at least one of whom showed reduced enzyme activity consistent with the condition. In at least 4 of these individuals, the p.Arg473His was identified with a potentially disease causing variant in ACADVL, and the variants were confirmed to be in trans in at least 1 individual (Andresen 1999 PMID: 9973285, Fukao 2001 PMID: 11158518, Smelt 1998 PMID: 9546340, Ohashi 2004 PMID: 15210884, Osawa 2022 PMID: 35400565). This variant has also been identified in 0.01% (6/44888) of East Asian chromosomes by gnomAD, including 1 homozygote in the South Asian population (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies of enzymatic activity and protein expression provide some evidence that this variant impacts protein function (Fukao 2001 PMID: 11158518; Ohashi 2004 PMID: 15210884; Osawa 2022 PMID: 35400565) and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Additionally, this variant was classified as likely pathogenic on Dec 14, 2022 by the ClinGen-approved ACADVL Variant Curation Expert Panel (Variation ID 1634). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting, PP4, PP3, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2023	Variant summary: ACADVL c.1349G>A (p.Arg450His) 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 2.4e-05 in 251342 control chromosomes (gnomAD). c.1349G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Fukao_2001, Osawa_2022), and some were compound heterozygous with other (likely) pathogenic variants. 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, finding that the variant results in <10% of normal activity (Fukao_2001). Seven submitters, including a ClinGen expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 31130284, 30840296, 11158518, 20060901, 24801231, 29519241, 28980192, 29552494, 27246109, 25652019, 9973285, 9546340, 15210884) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 23, 2018	The ACADVL c.1349G>A; p.Arg450His variant (rs118204016), also known as Arg410His for traditional nomenclature, is reported multiple times in the literature in association with VLCAD deficiency and is reported both in the homozygous and compound heterozygous states in affected individuals (Andresen 1999, Fukao 2001, Gobin-Limballe 2010, Kang 2018, Ohashi 2004, Smelt 1998, Zhang 2014). Additionally, functional analyses of the variant protein show decreased expression and enzymatic activity (Fukao 2001, Smelt 1998). This variant is reported in ClinVar (Variation ID: 1634) and found in the general population with a low overall allele frequency of 0.003% (8/277108 alleles) in the Genome Aggregation Database. The arginine at codon 450 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Andresen BS 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. Fukao T et al. Myopathic form of very-long chain acyl-coa dehydrogenase deficiency: evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl. Pediatr Res. 2001 Feb;49(2):227-31. 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. Kang E et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 2018 Mar 8;18(1):103. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13. Smelt AH et al. Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol. 1998 Apr;43(4):540-4. Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25. -

Rhabdomyolysis;C4023591:Abnormal circulating enzyme concentration

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.93

.;D;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.5

D;.;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.88

MutPred

0.96

.;Loss of MoRF binding (P = 0.0708);.;

MVP

1.0

MPC

0.85

ClinPred

0.95

GERP RS

4.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.89

gMVP

0.94

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.

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