rs1057516686

Positions:

• chr17-7222864-CGG-CCAC
• chr17-7222864-CGG-CG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4 PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID:9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1,PM2_supporting,PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041866/MONDO:0008723/021

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADVL NM_000018.4 splice_donor, coding_sequence
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 6.62

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 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1077_1077+1delinsCAC		splice_donor_variant, coding_sequence_variant	10/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1077_1077+1delinsCAC		splice_donor_variant, coding_sequence_variant	10/20	1	NM_000018.4	ENSP00000349297	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: Pathogenic

Submissions summary: Pathogenic:8

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	Baylor Genetics	Sep 13, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2018	Variant summary: ACADVL c.1077_1077+1delinsCAC is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244794 control chromosomes (gnomAD). The variant, c.1077_1077+1delinsCAC, has been reported in the literature in one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in whom no second allele was reported so the exact genotype could not be inferred (Andresen_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 10 (c.1077_1077+1delinsCAC) of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). -
Pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 20, 2022	The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID: 9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1,PM2_supporting,PP4). -
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.1077_1077+1delinsCAC (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222865_7222866delinsCAC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -

ACADVL-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2023

The ACADVL c.1077_1077+1delinsCAC variant is predicted to result in an in-frame deletion and insertion. This change is predicted to abolish the canonical splice donor site. This variant was reported in an individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al. 1999. PubMed ID: 9973285; Intron 10 GG>CAC). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Canonical-splice altering variants in ACADVL are expected to be pathogenic, including several others reported at this same splice junction. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057516686; hg19: chr17-7126184;