Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001908838 | SCV002171338 | uncertain significance | not provided | 2021-05-21 | criteria provided, single submitter | clinical testing | 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. 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 expected to disrupt CTSK protein function. This variant has been observed in individual(s) with pycnodysostosis (PMID: 24767306). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 169 of the CTSK protein (p.Asp169Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. |
| Gene |
RCV001908838 | SCV005325154 | likely pathogenic | not provided | 2024-02-05 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35186389, 28651365, 24767306, 37809147) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004770271 | SCV005381033 | pathogenic | Pyknodysostosis | 2024-08-15 | criteria provided, single submitter | clinical testing | Variant summary: CTSK c.505G>A (p.Asp169Asn) results in a conservative amino acid change located in the Peptidase C1A, papain C-terminal domain (IPR000668) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.505G>A has been reported in the literature in multiple homozygous individuals affected with Pyknodysostosis (e.g. Arman_2014, Unsal_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37809147, 24767306). ClinVar contains an entry for this variant (Variation ID: 1403033). Based on the evidence outlined above, the variant was classified as pathogenic. |