rs28934585

Positions:

chr17-7220519-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BS3_SupportingBA1BP4

This summary comes from the ClinGen Evidence Repository: The c.194C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 65 (p.Pro65Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1129 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Palmitoyl-CoA dehydrogenase activity in VLCAD-null fibroblasts transfected with c.194C>T cDNA showed activity comparable to the cells transfected with wild-type cDNA indicating that this variant does not impact protein function (PMID:10790204, BS3_supporting). The computational predictor REVEL gives a score of 0.276, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BS3_supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA285292/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.032 ( 248 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 246 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -1.74

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 Benign. Variant got -10 ACMG points.

BP4

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

BS3

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

BA1

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.194C>T	p.Pro65Leu	missense_variant	3/20	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.194C>T	p.Pro65Leu	missense_variant	3/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4888

AN:

152190

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.00823

AC:

2069

AN:

251436

Hom.:

102

AF XY:

0.00600

AC XY:

816

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.00520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00323

AC:

4719

AN:

1461878

Hom.:

246

Cov.:

AF XY:

0.00278

AC XY:

2023

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.110

Gnomad4 AMR exome

AF:

0.00635

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.00798

GnomAD4 genome

AF:

0.0321

AC:

4895

AN:

152308

Hom.:

248

Cov.:

AF XY:

0.0311

AC XY:

2315

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.111

Gnomad4 AMR

AF:

0.0139

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.00985

Hom.:

Bravo

AF:

0.0362

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0992

AC:

437

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0105

AC:

1273

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Benign:6

Benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Mar 08, 2022	The c.194C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 65 (p.Pro65Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1129 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Palmitoyl-CoA dehydrogenase activity in VLCAD-null fibroblasts transfected with c.194C>T cDNA showed activity comparable to the cells transfected with wild-type cDNA indicating that this variant does not impact protein function (PMID: 10790204, BS3_supporting). The computational predictor REVEL gives a score of 0.276, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BS3_supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 09, 2020	- -
Benign, 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.194C>T (NP_000009.1:p.Pro65Leu) [GRCH38: NC_000017.11:g.7220519C>T] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2013	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 27, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.29

CADD

Benign

3.9

DANN

Benign

0.71

DEOGEN2

Benign

0.25

.;T;.;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.40

T;T;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.95

.;L;.;.;.

MutationTaster

Benign

1.8e-8

A;A;A

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.9

N;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.047

D;.;.;.;.

Sift4G

Benign

0.14

T;T;T;T;D

Polyphen

0.019

.;B;.;.;.

Vest4

0.11

MPC

0.20

ClinPred

0.017

GERP RS

-7.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.025

gMVP

0.28

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