rs118204014

chr17-7224966-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000018.4(ACADVL):c.1837C>T(p.Arg613Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,950 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R613Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 1.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7224967-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 618502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 17-7224966-C-T is Pathogenic according to our data. Variant chr17-7224966-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1623.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7224966-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1837C>T	p.Arg613Trp	missense_variant	20/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1837C>T	p.Arg613Trp	missense_variant	20/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000518 AC: 13 AN: 251108 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135812

Gnomad AFR exome AF: 0.0000616

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: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461780 Hom.: 0 Cov.: 35 AF XY: 0.0000261 AC XY: 19 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000333

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

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: 0.000155 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:13

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 613 of the ACADVL protein (p.Arg613Trp). This variant is present in population databases (rs118204014, gnomAD 0.009%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (PMID: 7479827, 8554073, 10077518, 17999356, 19327992). ClinVar contains an entry for this variant (Variation ID: 1623). 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: 8554073, 17374501). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 20, 2018	The ACADVL c.1837C>T (p.Arg613Trp) variant has been reported in at least four studies and is found in a total of five probands with VLCAD deficiency including two in a homozygous state and three in a compound heterozygous state (Strauss et al. 1995; Gobin-Limballe et al. 2007; Laforet et al. 2009; Bouvier et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of proband fibroblasts reported by revealed significantly lower VLCAD enzyme activity and no detectable ACADVL protein (Hale et al. 1985; Strauss et al. 1995; Aoyama et al. 1995). Souri et al. (1996) reported the p.Arg613Trp variant protein expressed in CHO cells had significantly less protein accumulation when compared to wild type despite normal mRNA levels, reduced VLCAD activity, and failure to homodimerize. Further, Goetzman et al. (2007) used a bacterial expression system to confirm that the p.Arg613Trp variant protein has no VLCAD activity. Based on the evidence, the p.Arg613Trp 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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 11, 2019	The ACADVL c.1837C>T; p.Arg613Trp variant (rs118204014), also published as Arg573Trp, is reported in the literature in individuals affected with very-long chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency (Gobin-Limballe 2007, Laforet 2009, Strauss 1995, Souri 1996). In multiple affected patients, this variant was observed in trans to a second pathogenic variant (Gobin-Limballe 2007, Strauss 1995, Souri 1996). This variant is found in the general population with an overall allele frequency of 0.005% (14/282476 alleles) in the Genome Aggregation Database, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 1623). The arginine at codon 613 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is deleterious. Additionally, several publications have shown that this variant results in reduced dimerization and enzyme function (Gobin-Limballe 2007, Goetzman 2007, Souri 1996). Taken together, the p.Arg613Trp variant is considered pathogenic. References: Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007 Dec;81(6):1133-43. Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. 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 May;19(5):324-9. Souri M et al. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 Jan;58(1):97-106. Strauss AW et al. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10496-500. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 01, 2022	Variant summary: ACADVL c.1837C>T (p.Arg613Trp) results in a non-conservative amino acid change in 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 5.2e-05 in 251108 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (5.2e-05 vs 0.0029), allowing no conclusion about variant significance. c.1837C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Strauss_1995, Souri_1996, Gobin-Limballe_2007, Bouvier_2017, Olsson_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications have reported experimental evidence demonstrating that the variant protein has little to no enzymatic activity (0.2% of normal ACADVL) and provided data indicating that the variant strongly impacts either enzyme assembly or stability (e.g. Souri_1996, Goetzman_2007). Six assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2017	The p.Arg613Trp variant in ACADVL (also called p.Arg573Trp) has been reported in at least 4 individuals with clinical features of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. All four individuals were compound heterozygous with different pathogenic variants in ACADVL (Strauss 1995, Souri 1996, Andresen 1999, Gobin-Limballe 2007). In vitro functional studies provide evidence that the p.Arg613Trp variant may impact protein function resulting in little to no enzyme activity (Souri 1996, Goetzman 2007). However, these types of assays may not accurately represent biological function. This variant has been identified in 11/126434 of European by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204014). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner based upon case reports, low frequency in the general population and functional evidence. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 29, 2014	- -
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.1837C>T (NP_000009.1:p.Arg613Trp) [GRCH38: NC_000017.11:g.7224966C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 7479827. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Jun 13, 2023	The c.1837C>T variant in ACADVL is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 613 (p.Arg613Trp). This variant has been reported in ACADVL deficiency in numerous studies, including PMIDs:7479827, 8554073, 35281659, 17374501, 30194637. This variant is associated with increased C14:1 acylcarnitine levels in patients with ACADVL deficiency (PMID: 33986768, PP4_moderate). This variant was also detected in compound heterozygote with pathogenic variants from multiple patients (PM3, PMID: 7479827, 8554073, 30194637). This variant causes significantly reduced enzyme activity determined from lymphocytes, mammalian, and bacterial cell expression systems (PMID: 30194637, 8554073, 17374501, 33986768) and results in unstable protein product (PMID:8554073, PS3_supporting). This variant is also part of a C-terminal domain critical for mitochondiral membrane binding (PMID: 18227065). The highest population minor allele frequency in gnomAD is 0.0001 in the European non-Finnish population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary the ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PS3_supporting+PM3+PP3+PP4_moderate+PM2_supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2017

The R613W missense mutation identified in the ACADVL gene has been reported previously in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Strauss et al., 1995). Functional studies have shown that the R613W mutation significantly impacts enzyme activity (Goetzman et al., 2007). The The variant is found in ACADVL panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	27
Dann	Uncertain	0.97
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.85
MVP		0.96
MPC		0.78
ClinPred		0.72	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.90

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

Other links and lift over

dbSNP: rs118204014; hg19: chr17-7128285;