rs113994170

Positions:

• chr17-7224040-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PM2_Supporting PS3_Supporting PP4_Moderate PM1 PM3

This summary comes from the ClinGen Evidence Repository: The c.1405C>T variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 469 (p.Arg469Trp). This variant has been detected in at least 5 individuals with clinical signs of very long chain acyl CoA dehydrogenase (VLCAD) deficiency; 2 were heterozygous for the variant without an identified second distinct variant in ACADVL (PMIDs: 9973285, Olpin SE et al. Int J Neonat Screen. 2017 3(1),2); 3 individuals were homozygous for the variant (PM3 points = 1.0 max, PMID:9973285) (PM3). ACADVL activity in one patient's fibroblast cell line was observed at <=20% of normal (PMID:17999356) (PP4_Moderate). Expression of this variant using rACADVL in E. coli showed enzyme activity =< 20% of normal and absence of protein expression indicating that this variant impacts protein function (PMID:17374501) (PS3_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID:9973285) (PM1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 in the EAS 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 0.947, 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 very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM1, PS3_Supporting PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-13-2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341519/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.83

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1405C>T	p.Arg469Trp	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	c.1405C>T	p.Arg469Trp	missense_variant	14/20	1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251418 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000334 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 30, 2024	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Oct 12, 2022	The c.1405C>T variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 469 (p.Arg469Trp). This variant has been detected in at least 5 individuals with clinical signs of very long chain acyl CoA dehydrogenase (VLCAD) deficiency; 2 were heterozygous for the variant without an identified second distinct variant in ACADVL (PMIDs: 9973285, Olpin SE et al. Int J Neonat Screen. 2017 3(1),2); 3 individuals were homozygous for the variant (PM3 points = 1.0 max, PMID: 9973285) (PM3). ACADVL activity in one patient's fibroblast cell line was observed at <=20% of normal (PMID: 17999356) (PP4_Moderate). Expression of this variant using rACADVL in E. coli showed enzyme activity =< 20% of normal and absence of protein expression indicating that this variant impacts protein function (PMID: 17374501) (PS3_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285) (PM1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 in the EAS 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 0.947, 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 very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM1, PS3_Supporting PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-13-2022). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 469 of the ACADVL protein (p.Arg469Trp). This variant is present in population databases (rs113994170, gnomAD 0.01%). This missense change has been observed in individual(s) with very–long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 9973285, 17999356, 27246109). This variant is also known as R429W. ClinVar contains an entry for this variant (Variation ID: 21017). 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. Experimental studies have shown that this missense change affects ACADVL function (PMID: 17374501). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 16, 2020	The ACADVL c.1405C>T; p.Arg469Trp variant (rs113994170), also known as Arg429Trp, has been reported in multiple individuals with VLCAD deficiency, including three severely affected individuals that were homozygous for the variant (Andresen 1999). Additionally, functional studies have shown that the variant protein has significantly reduced enzymatic activity (Goetzman 2007, Hoffmann 2012). This variant is reported in ClinVar (Variation ID: 21017), and observed in the general population with low overall allele frequencies of 0.008 percent (1/13006 alleles, Exome Variant Server), and 0.003 percent (7/246250 alleles, Genome Aggregation Database). The arginine at codon 469 is well conserved across species, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered 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. 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. Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 21, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 21, 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.1405C>T (NP_000009.1:p.Arg469Trp) [GRCH38: NC_000017.11:g.7224040C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 30, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.97	.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.7	D;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.99
MVP		1.0
MPC		0.78
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113994170; hg19: chr17-7127359;