Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Strand Center for Genomics and Personalized Medicine, |
RCV000203523 | SCV000258909 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | criteria provided, single submitter | clinical testing | Though the observed variant has not been reported in a clinical context, an overlapping known missense variant, p.Arg567Gln was found to be associated with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) and was suggested to be present in the C-terminal region unique to ACADVL and ACAD9. In a cohort study consisting of 13 VLCADD patients, p.Arg567Gln variant was observed in a 6 years old male patient in a compound heterozygous state with p.Gly514Glu variant. Fatty acid oxidation probe assay in patient fibroblast reported elevated C14 , C12 and C16 levels but the patient was asymptomatic.The VLCAD activity assay and immunohistologic staining for VLCAD performed on patient fibroblasts reported that p.Arg567Gln variant caused loss of expression and exhibited partial activity as compared to wild type cells. Moreover, prokaryotic mutagenesis and expression studies done on E.coli revealed that p.Arg567Gln variant markedly decreased VLCAD antigen levels making it deleterious while p.Gly514Glu variant showed normal VLCAD antigen levels [PMID:23480858]. Thus, alteration of Arg-567 in both copies of the gene is likely to play a role severe clinical manifestation. The novel variant Arg567Trp, has a probable but no proven role in the disease manifestation; thus it has been classified as a VUS with a likely role in the observed clinical indication. | |
| Invitae | RCV000203523 | SCV002965967 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | 2022-08-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 567 of the ACADVL protein (p.Arg567Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 28600779). This variant is also known as c.1633C>T:p.R545W. ClinVar contains an entry for this variant (Variation ID: 219172). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg567 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23480858; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |