Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479383 | SCV000573811 | likely pathogenic | not provided | 2017-03-10 | criteria provided, single submitter | clinical testing | The c.1487 G>A variant in the ACE gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1487 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is predicted to destroy the natural splice donor site in intron 9, resulting in aberrant gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of RNA/functional studies, the actual effect of the c.1487 G>A change is unknown. If c.1487 G>A does not alter splicing, it will result in the R496Q missense change. The R496Q missense variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this missense variant is probably damaging to the protein structure/function. The c.1487 G>A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV000479383 | SCV002184817 | likely pathogenic | not provided | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 496 of the ACE protein (p.Arg496Gln). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs761345398, gnomAD 0.006%). This missense change has been observed in individual(s) with renal tubular dysgenesis (PMID: 30598831, 35286024). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 424035). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |