rs1555529186

Positions:

• chr17-7225007-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000356839.10(ACADVL):​c.1878G>A​(p.Trp626Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADVL ENST00000356839.10 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 0.415

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7225007-G-A is Pathogenic according to our data. Variant chr17-7225007-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541724.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1878G>A	p.Trp626Ter	stop_gained	20/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1878G>A	p.Trp626Ter	stop_gained	20/20	1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4 Uncertain:1

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.1878G>A (NP_000009.1:p.Trp626Ter) [GRCH38: NC_000017.11:g.7225007G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 26385305. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Val642Met) have been determined to be pathogenic (PMID: 31031081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 541724). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 32778825). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp626*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the ACADVL protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2024	Variant summary: ACADVL c.1878G>A (p.Trp626X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 30 amino acids of the protein. The variant was absent in 251306 control chromosomes (gnomAD). c.1878G>A has been reported in the literature in individuals undergoing newborn screening (e.g., Miller_2015, Adhikari_2020), however, the phenotype or if a second ACADVL variant was detected in trans in these individuals was not reported. These reports therefore do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 26385305). ClinVar contains an entry for this variant (Variation ID: 541724). Additionally, downstream variants have been reported in association with Very long chain acyl-CoA dehydrogenase deficiency in HGMD and have been classified as pathogenic/likely pathogenic by our laboratory and others in ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2019	The ACADVL c.1878G>A; p.Trp626Ter variant is reported in the medical literature in at least one individual sent for newborn screening of very-long-chain acyl-CoA dehydrogenase deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 541724), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a premature termination codon and truncates the terminal 30 amino acids. These amino acids are unique amongst acyl-CoA dehydrogenases, but have no reported critical function (Goetzman 2007, McAndrew 2008). Due to limited information, the clinical significance of the p.Trp626Ter variant is uncertain at this time. References: Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2022

Identified in an individual with a positive newborn screen for VLCAD deficiency (Miller et al., 2015); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26385305, 32778825) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Benign	0.94
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.68	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.34
GERP RS		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555529186; hg19: chr17-7128326;