rs118204018

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000018.4(ACADVL):c.1246G>A(p.Ala416Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,970 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. A416S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 8.82

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000018.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7223707-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553497.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 17-7223707-G-A is Pathogenic according to our data. Variant chr17-7223707-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1633.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1246G>A	p.Ala416Thr	missense_variant	12/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1246G>A	p.Ala416Thr	missense_variant	12/20	1	NM_000018.4	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

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:

0.000193

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251462

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 22, 2018	The ACADVL c.1246G>A (p.Ala416Thr) variant has been reported in at least four patients in a compound heterozygous state, two of whom had mild manifestation of VLCAD deficiency (Fukao et al. 2001; Takusa et al. 2002; Brown et al. 2014; Hesse et al. 2018). The p.Ala416Thr variant was absent from 100 controls and is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies used transient expression of the p.Ala416Thr variant and showed residual acyl-CoA dehydrogenase activity of 10-20% of wild type (Fukao et al. 2001). Based on the evidence, the ACADVL p.Ala416Thr variant is classified as likely pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Aug 09, 2022	The c.1246G>A (p.Ala416Thr) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 416. This variant has been reported in several individuals affected with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, with at least one individual showing VLCAD enzyme activity <20% of normal, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID: 15210884, 20060901, 11914034, 30194637). Additionally, this variant has been reported confirmed in trans to a likely pathogenic variant and presumed in trans to several distinct variants, at least one of which is pathogenic (PM3; PMIDs: 15210884, 20060901, 11914034, 30194637). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001591 in the total population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Functional assays of fibroblasts transfected with this variant showed reduced ACADVL enzyme function indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 11158518, 11914034). The computational predictor REVEL gives a score of 0.936, 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 VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel:PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 07, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADVL function (PMID: 11158518). 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. ClinVar contains an entry for this variant (Variation ID: 1633). This missense change has been observed in individual(s) with myopathic form of very-long chain acyl-CoA dehydrogenase deficiency (PMID: 11158518, 11914034, 15210884). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs118204018, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 416 of the ACADVL protein (p.Ala416Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2021	NM_000018.3(ACADVL):c.1246G>A(A416T) is a missense variant classified as likely pathogenic in the context of very long chain acyl-CoA dehydrogenase deficiency. A416T has been observed in cases with relevant disease (PMID: 15210884, 11158518, 11914034, Mitsui_2014_(no PMID; article), 30194637). Functional assessments of this variant are available in the literature (PMID: 11158518, 20060901, 21378393). A416T has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, NM_000018.3(ACADVL):c.1246G>A(A416T) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Nov 12, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Benign

0.97

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

D;.;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.97, 0.95

.;D;P

Vest4

0.97

MutPred

0.91

.;Gain of methylation at K419 (P = 0.1424);.;

MVP

0.97

MPC

0.35

ClinPred

0.91

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.87

gMVP

0.93

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