Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000187300 | SCV000240882 | uncertain significance | not provided | 2013-09-10 | criteria provided, single submitter | clinical testing | p.Ile384Val (ATC>GTC): c.1150 A>G in exon 9 of the CTSD gene (NM_001909.3). The Ile384Val missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. A missense mutation in the adjacent amino acid (Trp383Cys) has been published in a child with cathepsin D deficiency who also had a second mutation on the other allele (Steinfeld et al., 2006). The Ile384Val variant identified was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one uncharged, non-polar amino acid for another at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ile384Val is a disease-causing mutation or a rare benign variant.The variant is found in CHILD-EPI panel(s). |
Invitae | RCV002516988 | SCV003493521 | uncertain significance | Neuronal ceroid lipofuscinosis | 2022-10-01 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 384 of the CTSD protein (p.Ile384Val). This variant is present in population databases (rs767863175, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 205344). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CTSD 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. |