NM_000018.4:c.1375C>G

Variant names:

• chr17-7224010-C-G
• rs766742117
• NM_000018.4:c.1375C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000018.4(ACADVL):​c.1375C>G​(p.Arg459Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R459P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.39
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7224011-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541713.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-7224010-C-G is Pathogenic according to our data. Variant chr17-7224010-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 932769.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.1375C>G	p.Arg459Gly	missense	Exon 14 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1444C>G	p.Arg482Gly	missense	Exon 15 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1309C>G	p.Arg437Gly	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.1375C>G	p.Arg459Gly	missense	Exon 14 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1309C>G	p.Arg437Gly	missense	Exon 13 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1444C>G	p.Arg482Gly	missense	Exon 15 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Very long chain acyl-CoA dehydrogenase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Benign	0.76
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.90
Sift	Benign	0.036	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.97
MutPred		0.89		Loss of MoRF binding (P = 0.0357)
MVP		0.99
MPC		0.83
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.98

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: rs766742117; hg19: chr17-7127329;