rs864321651

Positions:

chr17-7224662-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000018.4(ACADVL):c.1699C>T(p.Arg567Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,342,862 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R567Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.67

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7224663-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1699C>T	p.Arg567Trp	missense_variant	18/20	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.1699C>T	p.Arg567Trp	missense_variant	18/20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

145926

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000372

AC:

AN:

1342862

Hom.:

Cov.:

AF XY:

0.00000452

AC XY:

AN XY:

663912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000324

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000383

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

145926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70878

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 567 of the ACADVL protein (p.Arg567Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 28600779). This variant is also known as c.1633C>T:p.R545W. ClinVar contains an entry for this variant (Variation ID: 219172). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg567 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23480858; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd	-	Though the observed variant has not been reported in a clinical context, an overlapping known missense variant, p.Arg567Gln was found to be associated with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) and was suggested to be present in the C-terminal region unique to ACADVL and ACAD9. In a cohort study consisting of 13 VLCADD patients, p.Arg567Gln variant was observed in a 6 years old male patient in a compound heterozygous state with p.Gly514Glu variant. Fatty acid oxidation probe assay in patient fibroblast reported elevated C14 , C12 and C16 levels but the patient was asymptomatic.The VLCAD activity assay and immunohistologic staining for VLCAD performed on patient fibroblasts reported that p.Arg567Gln variant caused loss of expression and exhibited partial activity as compared to wild type cells. Moreover, prokaryotic mutagenesis and expression studies done on E.coli revealed that p.Arg567Gln variant markedly decreased VLCAD antigen levels making it deleterious while p.Gly514Glu variant showed normal VLCAD antigen levels [PMID:23480858]. Thus, alteration of Arg-567 in both copies of the gene is likely to play a role severe clinical manifestation. The novel variant Arg567Trp, has a probable but no proven role in the disease manifestation; thus it has been classified as a VUS with a likely role in the observed clinical indication. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.87

.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.1

.;M;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.4

D;.;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.78

MutPred

0.80

.;Gain of catalytic residue at L565 (P = 0.0034);.;

MVP

0.99

MPC

0.78

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.95

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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