17-7223151-C-T

Position:

chr17-7223151-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000018.4(ACADVL):c.1096C>T(p.Arg366Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,734 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. R366H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:1

Conservation

PhyloP100: 2.96

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:

ACADVL (HGNC:):

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7223152-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 17-7223151-C-T is Pathogenic according to our data. Variant chr17-7223151-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1096C>T	p.Arg366Cys	missense_variant	11/20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1096C>T	p.Arg366Cys	missense_variant	11/20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251484

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74382

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:10Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 366 of the ACADVL protein (p.Arg366Cys). This variant is present in population databases (rs771874163, gnomAD 0.007%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, 9973285, 21932095; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg326Cys. ClinVar contains an entry for this variant (Variation ID: 203579). 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%. This variant disrupts the p.Arg366 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16488171, 20060901, 24263034, 27246109). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2022	The ACADVL c.1096C>T; p.Arg366Cys variant (rs771874163) has been reported in individuals with VLCAD deficiency (Andresen 1996) or in abnormal newborn results (Hoffmann 2012, Spiekerkoetter 2010). Analysis of enzymatic activity indicates that the variant protein has reduced activity compared to wildtype, with individuals showing residual activity less than 50 percent in fibroblasts (Hoffmann 2012) or lymphocytes (Spiekerkoetter 2010). This variant is also reported in ClinVar (Variation ID: 203579). It is only found on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 366 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.955). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996; 5(4):461-72. PMID: 8845838. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2):269-77. PMID: 21932095. Spiekerkoetter U et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr. 2010; 157(4):668-73. PMID: 20547398. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 23, 2020	The p.Arg366Cys variant (also described as p.Arg326Cys in the literature) in ACADVL has been previously reported in the compound heterozygous state in 1 individual with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) with at least 1 additional disease-causing variant (Andresen 1996 PMID 8845838). It has also been reported in the heterozygous state at least individual with VLCADD without a second ACADVL variant identified (Hoffman 2012 PMID 21932095). This variant has also been reported by other clinical laboratories in ClinVar and was identified in 0.002% of pan ethnic chromosomes in gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with a recessive carrier allele frequency. Functional studies using patient derived cell lines show reduced enzyme activity as well as reduced ACADVL protein levels (Andresen 1996 PMID 8845838, Andresen 1999 PMID 9973285, Hoffman 2012 PMID 21932095). Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, another variant involving this codon (p.Arg366His) has been identified in several individuals with VLCADD and has been classified as pathogenic by multiple clinical laboratories (Boneh 2006 PMID 16488171, Gobin-Llimballe 2020 PMID 20060901, Antunes 2013 PMID 24263034, Evans 2016 PMID 27246109, ClinVar Variation ID: 203580). 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 VLCADD. ACMG/AMP criteria applied: PM3_Supporting, PM2, PS3_Supporting, PP3, PM5. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jan 30, 2018	- -
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.1096C>T (NP_000009.1:p.Arg366Cys) [GRCH38: NC_000017.11:g.7223151C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 21, 2021	PS3, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ACADVL NM_000018.3 exon 11 p.Arg366Cys (c.1096C>T): This variant (also referred to as Arg326Cys) has been reported in the literature in the compound heterozygous state and in the heterozygous state with no second allele identified in several individuals affected with VLCAD deficiency (Andresen 1996 PMID:8845838, Andresen 1999 PMID:9973285, Hoffmann 2012 PMID:21932095). This variant is present in 0.006% (1/16256) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-7126470-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:203579). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, another variant at the same amino acid residue (Arg366His, also referred to as Arg362His) has been associated with disease, supporting the potential functional relevance of this codon. In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2023	Variant summary: ACADVL c.1096C>T (p.Arg366Cys) 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 2e-05 in 251484 control chromosomes (gnomAD). c.1096C>T has been reported in the literature in individuals that were clinically diagnosed or identified via newborn screening to be affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1996, Miller_2015, Maguolo_2020, Osawa_2022). These data indicate that the variant is likely to be associated with disease. Experimental evidence showed decreased enzyme activity in compound heterozygous individuals with the variant (e.g. Andresen_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8845838, 8739957, 32793418, 26385305, 35400565). A different variant affecting the same codon (c.1097G>A , p.Arg366His) has been classified pathogenic in ClinVar (CV ID 203580). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9973285, 8845838, 21932095, 26385305, 31980526) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2021	PS3, PM2, PM5, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.4

.;H;.

PrimateAI

Uncertain

0.62

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

0.98

MutPred

0.98

.;Loss of MoRF binding (P = 0.0286);.;

MVP

1.0

MPC

0.90

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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