17-7222866-G-T

Position:

chr17-7222866-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_SupportingPVS1

This summary comes from the ClinGen Evidence Repository: The c.1077+1G>T variant in ACADVL is a splice site variant affecting the canonical donor splice site in intron 10. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present at low frequency (1 allele, <0.1%) in large population database (PM2_supporting, gnomad). This variant has been reported in abnormal newborn screen with 36% residual enzyme activity (PP4 not met) without clinical confirmation or a second variant identified (PMID 21932095). In summary, this variant meets criteria to be classified as likely pathogenic for VLCAD in an AR manner. ACADVL-specific ACMG/AMP criteria applied: PVS1, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041867/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 6.62

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1077+1G>T		splice_donor_variant		ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1077+1G>T		splice_donor_variant		1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249894

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1458880

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725704

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects a donor splice site in intron 10 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 25338548, 30194637). ClinVar contains an entry for this variant (Variation ID: 370482). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2022	Variant summary: ACADVL c.1077+1G>T 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: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249894 control chromosomes. c.1077+1G>T has been reported in the literature in at least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency with residual enzyme activity of 36%. A second mutation was not identifed in this patient (Hoffmann_2012). The variant has also been reported in a patient with familial dilated cardiomyopathy, however co-occurrence with a pathogenic mutation in TTN (c.49458G>A, p.W16486X) was reported in this individual (Minoche_2019). These data do not allow any conclusion about variant significance. Four other 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, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 22, 2022	The c.1077+1G>T variant in ACADVL is a splice site variant affecting the canonical donor splice site in intron 10. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present at low frequency (1 allele, <0.1%) in large population database (PM2_supporting, gnomad). This variant has been reported in abnormal newborn screen with 36% residual enzyme activity (PP4 not met) without clinical confirmation or a second variant identified (PMID 21932095). In summary, this variant meets criteria to be classified as likely pathogenic for VLCAD in an AR manner. ACADVL-specific ACMG/AMP criteria applied: PVS1, PM2_supporting. -
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+1G>T (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222866G>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 19, 2021	NM_000018.3(ACADVL):c.1077+1G>T is a canonical splice variant classified as likely pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. c.1077+1G>T has been observed in cases with relevant disease (PMID: 21932095). Functional assessments of this variant are not available in the literature. c.1077+1G>T has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_000018.3(ACADVL):c.1077+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

ACADVL: PVS1, PM2, PP4:Moderate, PS1:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

D;D;D

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.48

Position offset: -30

DS_DL_spliceai

0.98

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over