Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000549650 | SCV000632507 | uncertain significance | Deficiency of butyryl-CoA dehydrogenase | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 154 of the ACADS protein (p.Leu154Phe). This variant is present in population databases (rs368500899, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ACADS-related conditions. ClinVar contains an entry for this variant (Variation ID: 460388). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADS protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003403272 | SCV004122370 | uncertain significance | not specified | 2023-10-04 | criteria provided, single submitter | clinical testing | Variant summary: ACADS c.460C>T (p.Leu154Phe) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.460C>T has been reported in the literature in the heterozygous state following WES in an individual with developmental delay (Salfati_2019). This report does not provide unequivocal conclusions about association of the variant with Deficiency Of Butyryl-CoA Dehydrogenase. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31847883). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |