rs118204017

Positions:

chr17-7224007-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PP4PM2_SupportingPM3_StrongPS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1372T>C variant is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 458 (p.Phe458Leu). This variant has also been published as Phe418Leu when numbered from the mature peptide. The c.1372T>C variant has been described in at least three individuals diagnosed with very long chain acyl CoA dehydrogenase (VLCAD), with at least two also carrying an additional pathogenic or likely pathogenic ACADVL variant confirmed in trans (PM3_Strong). At least one patient with this variant displayed VLCAD activity 20% of normal, which is highly specific for VLCAD deficiency (PP4; PMID:9709714). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001759 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Recombinant protein expressing this variant showed reduced VLCAD enzyme activity, indicating that this variant impacts protein function (PS3_Supporting; PMID:9461620). The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets 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: PM3_Strong, PP4, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251907/MONDO:0008723/021

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

9

4

6

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 6.84

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 Likely_pathogenic. Variant got 8 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1372T>C	p.Phe458Leu	missense_variant	14/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1372T>C	p.Phe458Leu	missense_variant	14/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152194

Hom.:

0

Cov.:

32

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

2

AN:

251414

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135898

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

7

AN:

1461870

Hom.:

0

Cov.:

33

AF XY:

0.00000275

AC XY:

2

AN XY:

727234

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:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152194

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74348

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:

0.0000147

Gnomad4 OTH

AF:

0.00

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:5

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.1372T>C (NP_000009.1:p.Phe458Leu) [GRCH38: NC_000017.11:g.7224007T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:9709714. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 14, 2022	The c.1372T>C variant is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 458 (p.Phe458Leu). This variant has also been published as Phe418Leu when numbered from the mature peptide. The c.1372T>C variant has been described in at least three individuals diagnosed with very long chain acyl CoA dehydrogenase (VLCAD), with at least two also carrying an additional pathogenic or likely pathogenic ACADVL variant confirmed in trans (PM3_Strong). At least one patient with this variant displayed VLCAD activity 20% of normal, which is highly specific for VLCAD deficiency (PP4; PMID: 9709714). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001759 in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Recombinant protein expressing this variant showed reduced VLCAD enzyme activity, indicating that this variant impacts protein function (PS3_Supporting; PMID: 9461620). The computational predictor REVEL gives a score of 0.828, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets 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: PM3_Strong, PP4, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 458 of the ACADVL protein (p.Phe458Leu). This variant is present in population databases (rs118204017, gnomAD 0.002%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 9709714, 10738914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1632). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 9709714, 10738914). For these reasons, this variant has been classified as Pathogenic. -

ACADVL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2024

The ACADVL c.1372T>C variant is predicted to result in the amino acid substitution p.Phe458Leu. This variant has been reported in the compound heterozygous state in two patients with clinical and biochemical features consistent with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), as well as reduced enzyme activity in fibroblasts (Cox et al. 1998. PubMed ID: 9709714; Pons et al. 2000. PubMed ID: 10738914, referred to as T1372C, Phe418Leu). In expression studies using baculovirus or Chinese hamster ovary cells, the p.Phe458Leu substitution was reported to lead to an inactive VLCAD enzyme lacking the FAD cofactor (Cox et al. 1998. PubMed ID: 9709714). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as likely pathogenic and pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1632/). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2023

Functional analysis found that this variant is associated with significantly reduced enzyme activity (PMID: 9709714); Not observed at a 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: 10738914, 9709714) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

27

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.89

.;D;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.58

D

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.59

D

MutationAssessor

Benign

0.48

.;N;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.72

T

PROVEAN

Pathogenic

-5.8

D;.;D

REVEL

Pathogenic

0.83

Sift

Benign

0.44

T;.;T

Sift4G

Benign

0.71

T;T;T

Polyphen

1.0, 0.49

.;D;P

Vest4

0.94

MutPred

0.82

.;Loss of MoRF binding (P = 0.1461);.;

MVP

0.96

MPC

0.83

ClinPred

0.74

D

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.92

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Other links and lift over

dbSNP: rs118204017; hg19: chr17-7127326;