chr17-7222854-A-G

Variant names:

• chr17-7222854-A-G
• rs150140386
• NM_000018.4:c.1066A>G

Variant summary

Our verdict is Uncertain significance. The variant received -7 ACMG points: 1P and 8B. BA1 PP4

This summary comes from the ClinGen Evidence Repository: The c.1066A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 356 (p.Ile356Val). Several individuals with this variant were identified by newborn screen, but this information is insufficient to use toward classification (PMID:30194637, 26385305, 23867825, 31031081, 27209629). One individual did display C14:1 level of 0.83, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4, PMID:31031081). At least one of these individuals carried an additional likely pathogenic variant not confirmed to be in trans, but this does not meet the criteria to be counted toward PM3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009786 in the African population with 3 total homozygotes, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). However, due to the possibility of this variant being enriched in an under-sequenced population, the ACADVL VCEP has overridden the BA1 evidence code to be in conflict with the specificity of the C14:1 level identified in an affected individual (PP4 data, PMID:31031081). Additionally, the ACADVL VCEP cannot exclude the possibility that the 3 homozygous individuals in gnomAD may be as-yet unaffected adults that could present with mild disease in the future. The computational predictor REVEL gives a score of 0.621, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. In summary, this variant meets the criteria to be classified as variant of uncertain significance 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, PP4 (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 December 10, 2025. LINK:https://erepo.genome.network/evrepo/ui/classification/CA200650/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5 B:6
• Conservation: PhyloP100: 4.01
• Publications: 11 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: ClinGen, G2P, Orphanet, 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.1066A>G	p.Ile356Val	missense	Exon 10 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1135A>G	p.Ile379Val	missense	Exon 11 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1000A>G	p.Ile334Val	missense	Exon 9 of 19	NP_001029031.1	P49748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1066A>G	p.Ile356Val	missense	Exon 10 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1000A>G	p.Ile334Val	missense	Exon 9 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1135A>G	p.Ile379Val	missense	Exon 11 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00906

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000850 AC: 213 AN: 250672 AF XY: 0.000590

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000296 AC: 432 AN: 1459908 Hom.: 1 Cov.: 32 AF XY: 0.000240 AC XY: 174 AN XY: 726248

African (AFR) AF: 0.0102 AC: 342 AN: 33436

American (AMR) AF: 0.000939 AC: 42 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.000212 AC: 1 AN: 4722

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111982

Other (OTH) AF: 0.000614 AC: 37 AN: 60270

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74444

African (AFR) AF: 0.00908 AC: 377 AN: 41524

American (AMR) AF: 0.000719 AC: 11 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00119 Hom.: 4

Bravo AF: 0.00317

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	5	2	Very long chain acyl-CoA dehydrogenase deficiency (7)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.62
Sift	Benign	0.067	T
Sift4G	Benign	0.062	T
Polyphen		0.98	D
Vest4		0.77
MVP		0.77
MPC		0.22
ClinPred		0.018	T
GERP RS		5.6
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.55
gMVP		0.55
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs150140386; hg19: chr17-7126173;