rs398123083

Variant names:

• chr17-7224041-G-A
• rs398123083
• NM_000018.4:c.1406G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PM3 PM1 PM5_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.1406G>A variant in ACADVL is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 469 (p.Arg469Trp). This variant has been detected in 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency; of the 3 homozygous individuals, 2 were monozygotic twins; in one heterozygous individual, a second distinct pathogenic variant in ACADVL was not observed. (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). (PM3 points = 1.0 max, PMIDs: 9973285, 17514507, 25834949) (PM3). At least one patient with this variant displayed ACADVL enzyme activity of <20% of normal which is highly specific for VLCADD (PP4_Moderate, PMID:25834949). Another missense variant c.1405C>T (p.Arg469Trp) [VCV000021017.19, PMIDs: 9973285, 17374501, 17999356] in the same codon has been classified as likely pathogenic for very long chain acyl CoA dehydrogenase (VLCAD) deficiency by the ClinGen ACADVL Variant Curation Expert Panel (PM5_Supporting). This variant resides at a CpG di-nucleotide of ACADVL that is defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID:9973285) (PM1). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC 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: PM3, PP4_Moderate, PM5, PM1, PM2_Supporting, PP3 (ClinGen ACADVL VCEP specifications version#1; 08-16-2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220197/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 8.54
• Publications: 7 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: 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.
• PM5: 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.

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.1406G>A	p.Arg469Gln	missense	Exon 14 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1475G>A	p.Arg492Gln	missense	Exon 15 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1340G>A	p.Arg447Gln	missense	Exon 13 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.1406G>A	p.Arg469Gln	missense	Exon 14 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1340G>A	p.Arg447Gln	missense	Exon 13 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1475G>A	p.Arg492Gln	missense	Exon 15 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Loss of MoRF binding (P = 0.0516)
MVP		0.99
MPC		0.81
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.87
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs398123083; hg19: chr17-7127360;