rs761204548
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PP4_ModeratePM3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL):c.799_802del (p.Val267GlnfsTer8) variant in ACADVL is a frameshift variant predicted cause a premature stop codon in biologically-relevant-exon 9/20 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 0.000003978 in general population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, of whom both were homozygous for the variant (PM3 score = 1.0, PM3, PMIDs: 27995075, 9973285). Patients with this variant displayed abnormal NBS and follow-up acylcarnitine profiles, and/or non-detectable ACADVL transcript by northern blot analysis, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMIDs: 27995075, 9973285). 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, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337855/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.799_802del | p.Val267GlnfsTer8 | frameshift_variant | 9/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.799_802del | p.Val267GlnfsTer8 | frameshift_variant | 9/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251386Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135888
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461820Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2017 | Variant summary: The ACADVL c.799_802delGTTA (p.Val267GlnfsX8) variant results in a premature termination codon, predicted to cause a truncated or absent ACADVL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.887_888delCT (p.Pro296fsX17) has been classified as likely pathogenicpathogenic by our laboratory. This variant was found in 1/246302 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADVL variant (0.0028868). Multiple publications have cited the variant in homozygous affected individuals. In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 28, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 08, 2016 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Jun 27, 2023 | The NM_000018.4(ACADVL):c.799_802del (p.Val267GlnfsTer8) variant in ACADVL is a frameshift variant predicted cause a premature stop codon in biologically-relevant-exon 9/20 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 0.000003978 in general population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, of whom both were homozygous for the variant (PM3 score = 1.0, PM3, PMIDs: 27995075, 9973285). Patients with this variant displayed abnormal NBS and follow-up acylcarnitine profiles, and/or non-detectable ACADVL transcript by northern blot analysis, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4, PMIDs: 27995075, 9973285). 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, PM3, PP4. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at