rs113690956

chr17-7223238-G-Achr17-7223238-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000018.4(ACADVL):c.1182+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000614 in 1,611,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: ACADVL NM_000018.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 6.93

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: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05284553 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of -13, new splice context is: gcaGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-7223238-G-A is Pathogenic according to our data. Variant chr17-7223238-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1622.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.1182+1G>A		splice_donor_variant		ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1182+1G>A		splice_donor_variant		1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152200 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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251464 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000651 AC: 95 AN: 1459140 Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 51 AN XY: 726090

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000188

Gnomad4 NFE exome AF: 0.0000820

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:10

Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 14, 2022	The c.1182+1G>A variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 11. It is predicted to cause skipping of biologically-relevant-exon 11/20, resulting in an in-frame deletion (removes amino acids 360-394) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The prediction of exon 11 skipping was confirmed by RT-PCR of fibroblasts from an individual homozygous for this variant; however, no VLCAD protein was detected (PMID:7479827). At least one patient with this variant displayed increased C14:1 acylcarnitines and reduced VLCAD activity in fibroblasts, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 23480858). This variant has been described in individuals identified by newborn screen, but this information is insufficient to use toward classification (PMID:26385305, 21932095). This variant has been described in affected individuals in the homozygous state and not confirmed in trans to a distinct variant of uncertain significance (PM3_Supporting; PMID: 7479827, 27209629, 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006154 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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: PVS1_Moderate, PP4_Moderate, PM3_Supporting, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2020	Variant summary: ACADVL c.1182+1G>A 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 2e-05 in 251464 control chromosomes. c.1182+1G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Strauss_1995, Pena_2016). At least one publication cites experimental evidence evaluating an impact on protein function. The most pronounced variant effect is cited as deficient mitochondrial dehydrogenase activity against palmitoyl-CoA, no immunoreactive VLCAD protein detected in fibroblast extracts and biosynthetic studies demonstrating rapid degradation of a slightly smaller, immunoreactive mutant VLCAD (Strauss_1995). Additionally, a residual enzyme activity of 50% has been reported as expected for a presumed carrier individual (Hoffmann_2012). Four 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 1995	- -
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.1182+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7223238G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:7479827. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 07, 2021	The ACADVL c.1182+1G>A variant (rs113690956), is reported in the literature in the homozygous or compound heterozygous state in individuals affected with very long-chain acyl-coenzyme A dehydrogenase deficiency (Hoffmann 2012, Pena 2016, Strauss 1995). This variant is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 11, which is likely to disrupt gene function. Based on available information, the c.1182+1G>A variant is considered to be pathogenic. References: Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Strauss AW et al. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10496-500. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 29, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change affects a donor splice site in intron 11 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 (rs113690956, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with VLCAD deficiency (PMID: 7479827, 27209629). This variant is also known as IVS11+1. ClinVar contains an entry for this variant (Variation ID: 1622). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects ACADVL function (PMID: 7479827, 21932095). 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, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 02, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26602010, 27209629, 21932095, 23480858, 7479827) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2021	PP4, PM2, PM3, PS3, PVS1_strong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs113690956; hg19: chr17-7126557;