rs1555529186
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
This summary comes from the ClinGen Evidence Repository: The c.1878G>A p.(Trp626Ter) variant in ACADVL is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate; PMIDs 9973285, 11590124). This variant has been reported in the literature in individuals undergoing newborn screening (PMIDs: 32778825, 26385305), however, the phenotype or if a second ACADVL variant was detected in trans in these individuals was not reported. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002891 in Admixed 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 variant of uncertain significance 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_Moderate, PM2_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA397726083/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- very long chain acyl-CoA dehydrogenase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461794Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727202 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5Uncertain:1
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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 -
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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. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 32778825). ClinVar contains an entry for this variant (Variation ID: 541724). 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. For these reasons, this variant has been classified as Pathogenic. -
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. -
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. -
not provided Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at