rs140566084

Variant names:

• chr17-7220796-A-G
• rs140566084
• NM_000018.4:c.308A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-7220796-A-G
• chr17-7220796-A-T

Variant summary

Our verdict is Uncertain significance. The variant received -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:10
• Conservation: PhyloP100: 1.20
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000018.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.308A>G	p.Lys103Arg	missense	Exon 5 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.377A>G	p.Lys126Arg	missense	Exon 6 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.242A>G	p.Lys81Arg	missense	Exon 4 of 19	NP_001029031.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.308A>G	p.Lys103Arg	missense	Exon 5 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.242A>G	p.Lys81Arg	missense	Exon 4 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.377A>G	p.Lys126Arg	missense	Exon 6 of 21	ENSP00000438689.2

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

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 251434 AF XY: 0.00106

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 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

African (AFR) AF: 0.0139 AC: 467 AN: 33480

American (AMR) AF: 0.00161 AC: 72 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.000446 AC: 496 AN: 1112004

Other (OTH) AF: 0.00192 AC: 116 AN: 60390

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

African (AFR) AF: 0.0116 AC: 481 AN: 41560

American (AMR) AF: 0.00333 AC: 51 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68022

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00195 Hom.: 6

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	5	Very long chain acyl-CoA dehydrogenase deficiency (6)
-	1	2	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0079	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.13	N
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.35
Sift	Benign	0.23	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs140566084; hg19: chr17-7124115; COSMIC: COSV107204098; COSMIC: COSV107204098;