rs796051917

chr17-7224860-GCT-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000018.4(ACADVL):c.1806_1807del(p.Cys603Ter) variant causes a frameshift change. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L602L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADVL NM_000018.4 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 6.51

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 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PP5: Variant 17-7224860-GCT-G is Pathogenic according to our data. Variant chr17-7224860-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203593.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.1806_1807del	p.Cys603Ter	frameshift_variant	19/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1806_1807del	p.Cys603Ter	frameshift_variant	19/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 31, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.1806_1807delCT (NP_000009.1:p.Cys603Ter) [GRCH38: NC_000017.11:g.7224863_7224864del] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 22, 2022	The c.1806_1807del (p.Leu602_Cys603insTer) variant in ACADVL is a frameshift variant that may cause loss of function of the protein due to impacting FAD interaction, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_moderate). Two siblings with this variant displayed C14:1 levels >0.8 µM, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 27209629). These same individuals were compound heterozygous for this variant and the pathogenic frameshift variant c.1173dup, however neither was confirmed in trans (PM3_supporting; PMID: 27209629). Finally, the variant segregates with VLCAD deficiency in the affected sibling (PP1; PMID: 27209629). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for VLCAD deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL VCEP: PVS1_moderate; PP4_moderate; PM3_supporting; PP1; PM2_supporting. Pilot Specifications; Approved on 05/12/2020. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Arg615*) have been determined to be pathogenic (PMID: 10431122). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 203593). This premature translational stop signal has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26385305, 27209629). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys603*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the ACADVL protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 21, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2013

The c.1806_1807delCT mutation causes the replacement of a Cysteine codon with a Stop codon at position 603, denoted p.Cys603Ter. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is predicted to be a pathogenic mutation. The variant is found in ACADVL panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs796051917; hg19: chr17-7128179;