Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000673234 | SCV004176830 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2022-12-14 | reviewed by expert panel | curation | The c.1770_1773del (p.Ser590fs) variant, also known as p.Ser590ArgfsTer89, in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 19/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed increased acylcarnitine levels, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 26927351). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000088 in the European (non-Finnish) 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 pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). |
Counsyl | RCV000673234 | SCV000798414 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2018-03-05 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000673234 | SCV000959497 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2018-11-15 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Arg613 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related disease (PMID: 10077518, 7479827, 19327992, 17999356, 8554073, 17374501), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has been observed in combination with another ACADVL variant in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26927351). ClinVar contains an entry for this variant (Variation ID: 557136). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ACADVL gene (p.Ser590Argfs*89). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acids of the ACADVL protein. |
Baylor Genetics | RCV000673234 | SCV004213721 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2022-11-28 | criteria provided, single submitter | clinical testing |