rs140566084

Positions:

• chr17-7220796-A-G

Variant summary

Our verdict is Uncertain significance. Variant got -7 ACMG points: 2P and 9B. BP4 BA1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.308A>G variant in ACADVL is a missense variant predicted to cause substitution of lysine by arginine at amino acid 103 (p.Lys103Arg). This variant has been reported in one individual with elevated C14:1 levels, an acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and a positive fatty acid oxidation probe assay, which are highly specific for VLCAD deficiency (PP4; PMID:27209629). The highest population minor allele frequency in gnomAD v2.1.1 is 1.2% in the African population, which is higher than the ClinGen ACADVL threshold (0.7%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.35, which is below the threshold of 0.5 indicating that the variant does not predict a damaging effect on ACADVL function (BP4). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for VLCAD deficiency, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on April 23, 2024. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337646/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (10 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:9
• Conservation: PhyloP100: 1.20

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]

ACMG classification

Verdict is Uncertain_significance. Variant got -7 ACMG points.

• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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	c.308A>G	p.Lys103Arg	missense_variant	5/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.308A>G	p.Lys103Arg	missense_variant	5/20	1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 571 AN: 152192 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251434 Hom.: 3 AF XY: 0.00106 AC XY: 144 AN XY: 135904

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000843 AC: 1232 AN: 1461784 Hom.: 10 Cov.: 33 AF XY: 0.000755 AC XY: 549 AN XY: 727176

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000446

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152310 Hom.: 3 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74484

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00121 Hom.: 3

Bravo AF: 0.00426

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Apr 23, 2024	The c.308A>G variant in ACADVL is a missense variant predicted to cause substitution of lysine by arginine at amino acid 103 (p.Lys103Arg). This variant has been reported in one individual with elevated C14:1 levels, an acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and a positive fatty acid oxidation probe assay, which are highly specific for VLCAD deficiency (PP4; PMID: 27209629). The highest population minor allele frequency in gnomAD v2.1.1 is 1.2% in the African population, which is higher than the ClinGen ACADVL threshold (0.7%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.35, which is below the threshold of 0.5 indicating that the variant does not predict a damaging effect on ACADVL function (BP4). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for VLCAD deficiency, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on April 23, 2024. -
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.308A>G (NP_000009.1:p.Lys103Arg) [GRCH38: NC_000017.11:g.7220796A>G] 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2022	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ACADVL: BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 17, 2022	Variant summary: ACADVL c.308A>G (p.Lys103Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251434 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.308A>G has been reported in the literature as a VUS in settings of newborn/presumptive screening for Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Miller_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as likely benign/benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	.;D;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.84	T;T;T;T;T
MetaRNN	Benign	0.0079	T;T;T;T;T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.13	.;N;.;.;.
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.60	N;.;.;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.23	T;.;.;T;.
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.0010, 0.0	.;B;.;B;.
Vest4		0.32
MVP		0.90
MPC		0.16
ClinPred		0.0076	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.35

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

Other links and lift over

dbSNP: rs140566084; hg19: chr17-7124115;