rs200573371

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP3_StrongPP5_Strong

The NM_000018.4(ACADVL):c.881G>A(p.Gly294Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,348 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. G294G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:4

Conservation

PhyloP100: 7.88

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000018.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 17-7222669-G-A is Pathogenic according to our data. Variant chr17-7222669-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 203575.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.881G>A	p.Gly294Glu	missense_variant, splice_region_variant	10/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.881G>A	p.Gly294Glu	missense_variant, splice_region_variant	10/20	1	NM_000018.4	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

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:

0.00000400

AC:

AN:

249786

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135094

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461124

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74434

show subpopulations

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

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:4Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2018	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Mar 28, 2023	The c.881G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 294 (p.Gly294Glu). At least two patients with this variant displayed low very long chain acyl-CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8739957, 12208138). This variant has been detected in at least three patients with clinically diagnosed VLCAD deficiency. Two of these individuals were compound heterozygous for this variant and a likely pathogenic variant, neither confirmed to be in trans (PM3_Supporting; PMID: 25737446,17999356). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL VCEP threshold (0.001) for PM2_supporting, meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.75, evidence that correlates with impact to VLCAD function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_moderate, PM2_supporting, PM3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). This variant was originally curated April 12, 2022 and the recurated classification was approved by the expert panel on March 28, 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.881G>A (NP_000009.1:p.Gly294Glu) [GRCH38: NC_000017.11:g.7222669G>A] 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, PP3. PP4 -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 06, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 294 of the ACADVL protein (p.Gly294Glu). This variant is present in population databases (rs200573371, gnomAD 0.0009%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 8739957, 12208138, 17999356). ClinVar contains an entry for this variant (Variation ID: 203575). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17999356, 12208138, 8739957) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 12, 2017	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2021

The c.881G>A (p.G294E) alteration is located in exon 10 (coding exon 10) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 881, causing the glycine (G) at amino acid position 294 to be replaced by a glutamic acid (E). This variant was identified in individuals with very long-chain acyl-CoA dehydrogenase deficiency in conjunction with a second ACADVL variant (Andresen, 1996; Giak Sim, 2002; Gobin-Limballe, 2007). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.4

D;.;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.95

MVP

0.99

MPC

0.88

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.96

gMVP

0.92

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

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