rs1057516370

Positions:

• chr17-7222867-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2_Supporting PM3_Supporting PVS1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000018.4:c.1077+2T>C variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, 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 has been detected in three homozygous siblings with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who inherited the variant from heterozygous parents (PMID:25338548)(PM3_Supporting, points=0.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two patients with this variant displayed elevated C14:1 levels ≥ 1.0 μM and VLCAD enzyme activity <20% of control in proband fibroblast (PMID:25338548, 9973285), which is highly specific for VLCADD (PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM2_supporting,PM3_Supporting, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041868/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADVL NM_000018.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 5.11

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 12 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.
• PM3: 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+2T>C		splice_donor_variant		ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1077+2T>C		splice_donor_variant		1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458666 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725616

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 17, 2021	NM_000018.3(ACADVL):c.1077+2T>C is a canonical splice variant classified as pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. c.1077+2T>C has been observed in cases with relevant disease (PMID: 9973285, 25338548). Functional assessments of this variant are available in the literature (PMID: 25338548). c.1077+2T>C has not been observed in population frequency databases. In summary, NM_000018.3(ACADVL):c.1077+2T>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 9973285, 25338548, 30194637). ClinVar contains an entry for this variant (Variation ID: 370279). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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+2T>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222867T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 25338548. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 29, 2020	Variant summary: ACADVL c.1077+2T>C 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: Three predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249894 control chromosomes. c.1077+2T>C has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency with a characteristic acyl-carnitine profile (example, Andersen_1999, Scalais_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Scalais_2015). This relatively high VLCAD activity in lymphocytes was attributed to oral riboflavin supplementation at the time of analysis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 29, 2022	The NM_000018.4:c.1077+2T>C variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, 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 has been detected in three homozygous siblings with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who inherited the variant from heterozygous parents (PMID:25338548)(PM3_Supporting, points=0.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two patients with this variant displayed elevated C14:1 levels ≥ 1.0 μM and VLCAD enzyme activity <20% of control in proband fibroblast (PMID:25338548, 9973285), which is highly specific for VLCADD (PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM2_supporting,PM3_Supporting, PP4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 25, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: 23
DS_DL_spliceai		0.97		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057516370; hg19: chr17-7126186;