rs1057517281

chr17-7223193-CAGG-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000018.4(ACADVL):c.1141_1143del(p.Glu381del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q380Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACADVL NM_000018.4 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 8.78

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000018.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-7223193-CAGG-C is Pathogenic according to our data. Variant chr17-7223193-CAGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 371449.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1141_1143del	p.Glu381del	inframe_deletion	11/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1141_1143del	p.Glu381del	inframe_deletion	11/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Aug 09, 2022	The c.1141_1143delGAG variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu381del) (PM4). The variant is reported in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (PMID: 25834949, 24305961, 21814341, 8845838). Six individuals were reported to have both elevated C14:1 levels and reduced VLCAD enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8845838, 21814341, 24305961, 25834949, 31031081). Of these individuals, one individual was homozygous for this variant, at least two of the individuals also carried an additional pathogenic variant not confirmed in trans, and at least four confirmed in trans to variants not yet curated by the VCEP (PM3; PMID: 24305961, 25834949, 32276429). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within a region of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_supporting, PM3, PM4, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2024	Variant summary: ACADVL c.1141_1143delGAG (p.Glu381del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251488 control chromosomes (gnomAD). c.1141_1143delGAG has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (examples: Andresen_1996, Pervaiz_2011, Diekman_2016, Rovelli_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8845838, 26881790, 21814341, 31031081). ClinVar contains an entry for this variant (Variation ID: 371449). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This variant, c.1141_1143del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu381del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, 21814341, 31031081). ClinVar contains an entry for this variant (Variation ID: 371449). Studies have shown that this variant alters ACADVL gene expression (PMID: 8845838). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517281; hg19: chr17-7126512;