rs864321651

Variant names:

• chr17-7224662-C-T
• rs864321651
• NM_000018.4:c.1699C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000018.4(ACADVL):​c.1699C>T​(p.Arg567Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,342,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R567Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 3.67
• Publications: 2 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7224663-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92278.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 17-7224662-C-T is Pathogenic according to our data. Variant chr17-7224662-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219172.

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.1699C>T	p.Arg567Trp	missense	Exon 18 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.1768C>T	p.Arg590Trp	missense	Exon 19 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.1633C>T	p.Arg545Trp	missense	Exon 17 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.1699C>T	p.Arg567Trp	missense	Exon 18 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.1633C>T	p.Arg545Trp	missense	Exon 17 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.1768C>T	p.Arg590Trp	missense	Exon 19 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 145926 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 176852 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000372 AC: 5 AN: 1342862 Hom.: 0 Cov.: 39 AF XY: 0.00000452 AC XY: 3 AN XY: 663912

African (AFR) AF: 0.00 AC: 0 AN: 30364

American (AMR) AF: 0.00 AC: 0 AN: 35614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22666

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30904

South Asian (SAS) AF: 0.00 AC: 0 AN: 80704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4720

European-Non Finnish (NFE) AF: 0.00000383 AC: 4 AN: 1044448

Other (OTH) AF: 0.00 AC: 0 AN: 53638

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 145926 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70878

African (AFR) AF: 0.00 AC: 0 AN: 39914

American (AMR) AF: 0.00 AC: 0 AN: 14640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 4752

South Asian (SAS) AF: 0.00 AC: 0 AN: 4358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66048

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Very long chain acyl-CoA dehydrogenase deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.80		Gain of catalytic residue at L565 (P = 0.0034)
MVP		0.99
MPC		0.78
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.91
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs864321651; hg19: chr17-7127981; COSMIC: COSV50035625; COSMIC: COSV50035625;