17-7224379-C-T

Position:

chr17-7224379-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000018.4(ACADVL):c.1591C>T(p.Arg531Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:10

Conservation

PhyloP100: 3.29

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-7224379-C-T is Pathogenic according to our data. Variant chr17-7224379-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166647.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=9, Pathogenic=1, Likely_pathogenic=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.29185665). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1591C>T	p.Arg531Trp	missense_variant	16/20	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.1591C>T	p.Arg531Trp	missense_variant	16/20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000444

AC:

111

AN:

250116

Hom.:

AF XY:

0.000450

AC XY:

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000934

Gnomad NFE exome

AF:

0.000806

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000852

AC:

1245

AN:

1461564

Hom.:

Cov.:

AF XY:

0.000842

AC XY:

612

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000355

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000507

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:3Uncertain:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 531 of the ACADVL protein (p.Arg531Trp). This variant is present in population databases (rs146379816, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 31031081; 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.Arg491Trp. ClinVar contains an entry for this variant (Variation ID: 166647). 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 80%. This variant disrupts the p.Arg531 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 27209629), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 14, 2021	The ACADVL c.1591C>T; p.Arg531Trp variant (rs146379816), also reported as p.Arg491Trp, is reported in the literature in the heterozygous state or in one case with a second variant presumed to be on the opposite chromosome in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (Adhikari 2020, Ghosh 2017, Hoffmann 2012, Rovelli 2019). This variant is also reported in ClinVar (Variation ID: 166647), and is found in the non-Finnish European population with an allele frequency of 0.076% (98/128338 alleles) in the Genome Aggregation Database. The arginine at codon 531 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.522). Due the limited amount of clinical and functional data, the significance of the p.Arg531Trp variant is uncertain at this time. References: Adhikari A et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020 Sep;26(9):1392-1397. PMID: 32778825. Ghosh A et al. Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing. Arch Dis Child. 2017 Nov;102(11):1019-1029. PMID: 28468868. 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. PMID: 21932095. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2023	- -
Likely 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.1591C>T (NP_000009.1:p.Arg531Trp) [GRCH38: NC_000017.11:g.7224379C>T] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM3, PP3, PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000018.3(ACADVL):c.1591C>T(R531W) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. R531W has been observed in cases with relevant disease (PMID: 31031081, 28468868). Functional assessments of this variant are not available in the literature. R531W has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1591C>T(R531W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 10, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 09, 2018	The ACADVL c.1591C>T (p.Arg531Trp) variant is a missense variant that has been reported in a compound heterozygous state with a canonical splice site variant in one individual with VLCAD deficiency who had residual enzyme activity of 21% (Hoffman et al. 2017). It has also been identified in a heterozygous state in four individuals with suspected VLCAD deficiency in whom a second variant was not identified (Miller et al. 2015; Ghosh et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000806 in the European (non-Finnish) population of the the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg531Trp variant is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2024	Variant summary: ACADVL c.1591C>T (p.Arg531Trp) results in a non-conservative amino acid change located in the ACAD9/ACADV-like, C-terminal domain (IPR049448) 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 0.00044 in 250116 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00044 vs 0.0029), allowing no conclusion about variant significance. c.1591C>T has been reported in the literature as a biallelic genotype in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Hoffmann_2012, Rovelli_2019, Olsson_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21932095, 28468868, 26385305, 31031081, 35281659, 34437764). ClinVar contains an entry for this variant (Variation ID: 166647). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.1591C>T (p.R531W) alteration is located in exon 16 (coding exon 16) of the ACADVL gene. This alteration results from a C to T substitution at nucleotide position 1591, causing the arginine (R) at amino acid position 531 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.044% (123/281458) total alleles studied. The highest observed frequency was 0.076% (98/128338) of European (non-Finnish) alleles. This variant has been detected in conjunction with multiple ACADVL variants in individuals with clinical and biochemical features of VLCAD deficiency (Hoffmann, 2012; Rovelli, 2019; Olsson, 2022). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 25, 2013

- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Uncertain

0.65

.;D;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.8

.;L;.

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0080

D;.;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.55

MVP

0.95

MPC

0.64

ClinPred

0.11

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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