rs387906249

chr17-7220922-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_000018.4(ACADVL):c.343del variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ACADVL NM_000018.4 splice_acceptor
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 8.70

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 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06808943 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 0 (no position change), new splice context is: ggatcctgtgccttccccAGaag. Cryptic site results in inframe 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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-7220922-AG-A is Pathogenic according to our data. Variant chr17-7220922-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 1624.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7220922-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.343del		splice_acceptor_variant		ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.343del		splice_acceptor_variant		1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135894

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727168

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000387

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

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: 0.000142 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:10

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 24, 2023	The ACADVL c.343del; p.Glu115LysfsTer2 variant (rs387906249) is reported in both homozygous and compound heterozygous individuals with VLCAD deficiency (Olsson 2022, Rovelli 2019, Strauss 1995). This variant is also classified as pathogenic by an expert panel (ClinVar Variation ID: 1624). It is only found on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Olsson D et al. Very long-chain acyl-CoA dehydrogenase deficiency in a Swedish cohort: Clinical symptoms, newborn screening, enzyme activity, and genetics. JIMD Rep. 2022 Jan 9;63(2):181-190. PMID: 35281659. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. 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. PMID: 7479827. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2020	Variant summary: ACADVL c.343delG (p.Glu115LysfsX2 also referred to as c.343-1delG) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant also deletes a conserved exonic nucleotide located adjacent to intron 5 splice acceptor site of the ACADVL gene: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 277170 control chromosomes (gnomAD). c.343delG has been reported in the literature in multiple compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency ( example, Strauss 1995, Mathur 1999, Evans 2016, Gillingham 2017, Ndukwe Erlingsson 2013, Olpin 2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function (example, Hesse 2018, Mathur 1999, Strauss 1995). The most pronounced variant effect results in <10% of normal activity in cell lines bearing this variant as a compound heterozygous genotype, while the variant results in 32% of normal activity in heterozygous patient fibroblasts. 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 (n=2)/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2021	- -
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.343delG (NP_000009.1:p.Glu115LysfsTer2) [GRCH38: NC_000017.11:g.7220924delG] 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, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Nov 09, 2021	The NM_000018.4(ACADVL): c.343del (p.Glu115Lysfs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant, however it has been reported in the literature in at least four individuals with VLCADD (PP4: PMID: 7479827, 31031081, 32778825). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PP4.) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Glu115Lysfs*2) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs387906250, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with very long chain acyl-CoA dehydrogenase (PMID: 23867825, 27246109). ClinVar contains an entry for this variant (Variation ID: 1624). 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2018	The c.343delG variant in the ACADVL gene has been reported previously in association with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Strauss et al., 1995; Ndukwe et al., 2013; Evans et al., 2016). The c.343delG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.343delG variant causes a frameshift starting with codon Glutamic Acid 115, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Glu115LysfsX2. The c.343delG variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.343delG as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2022

The c.343delG (p.E115Kfs*2) alteration, located in exon 6 (coding exon 6) of the ACADVL gene, consists of a deletion of one nucleotide at position 343, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.343delG allele has an overall frequency of 0.001% (4/282800) total alleles studied. The highest observed frequency was 0.004% (1/24962) of African alleles. This variant has been identified homozygous or with a second ACADVL variant in multiple individuals diagnosed with very long chain acyl-CoA dehydrogenase deficiency (Ndukwe Erlingsson, 2013; Miller, 2015; Evans, 2016; Gillingham, 2017; Elizondo, 2020; Vallejo, 2021; Olsson, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: 3
DS_AL_spliceai		0.98		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: rs387906249; hg19: chr17-7124241;