17-7224711-C-G

Variant names:

• chr17-7224711-C-G
• rs1085307648
• NM_000018.4:c.1748C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000018.4(ACADVL):​c.1748C>G​(p.Ser583Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000554 in 1,444,792 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S583L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 4.72
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7224710-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2860054.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 17-7224711-C-G is Pathogenic according to our data. Variant chr17-7224711-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1748C>G	p.Ser583Trp	missense	Exon 18 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1817C>G	p.Ser606Trp	missense	Exon 19 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1682C>G	p.Ser561Trp	missense	Exon 17 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.1748C>G	p.Ser583Trp	missense	Exon 18 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1682C>G	p.Ser561Trp	missense	Exon 17 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1817C>G	p.Ser606Trp	missense	Exon 19 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1444792 Hom.: 0 Cov.: 36 AF XY: 0.00000557 AC XY: 4 AN XY: 717598

African (AFR) AF: 0.00 AC: 0 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 42274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38734

South Asian (SAS) AF: 0.00 AC: 0 AN: 84552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1103660

Other (OTH) AF: 0.00 AC: 0 AN: 59590

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	1	-	Very long chain acyl-CoA dehydrogenase deficiency (6)
1	-	-	ACADVL-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Benign	0.93
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.51		Loss of disorder (P = 0.0028)
MVP		0.98
MPC		0.91
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.92
Mutation Taster		=1/99	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: rs1085307648; hg19: chr17-7128030;