chr17-7222668-G-GGGCC
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_SupportingPVS1
This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.881_884dup (p.Pro296AlafsTer3) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the Latino 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 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. (ACADVL VCEP specifications version 1; approved February 28, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337899/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.881_884dup | p.Pro296AlafsTer3 | frameshift_variant, splice_region_variant | 10/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.881_884dup | p.Pro296AlafsTer3 | frameshift_variant, splice_region_variant | 10/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249686Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135068
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461038Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726732
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 24, 2024 | - - |
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.881_884dupGGCC (NP_000009.1:p.Pro296AlafsTer3) [GRCH38: NC_000017.11:g.7222669_7222672dup] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change creates a premature translational stop signal (p.Pro296Alafs*3) 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 (rs766192888, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 371464). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 04, 2016 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Feb 28, 2023 | The NM_000152.5: c.881_884dup (p.Pro296AlafsTer3) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 in the Latino 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 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. (ACADVL VCEP specifications version 1; approved February 28, 2023) - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26385305) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at