Submissions for variant NM_000396.4(CTSK):c.908G>A (p.Gly303Glu)

dbSNP: rs756250449

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002648199	SCV003523444	pathogenic	not provided	2024-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 303 of the CTSK protein (p.Gly303Glu). This variant is present in population databases (rs756250449, gnomAD 0.01%). This missense change has been observed in individual(s) with pycnodysostosis (PMID: 21099701). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2202838). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTSK function (PMID: 30199612). This variant disrupts the p.Gly303 amino acid residue in CTSK. Other variant(s) that disrupt this residue have been observed in individuals with CTSK-related conditions (PMID: 21099701, 33945887), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239706	SCV005883255	pathogenic	Pyknodysostosis	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: CTSK c.908G>A (p.Gly303Glu) results in a non-conservative amino acid change in 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 2e-05 in 251410 control chromosomes (gnomAD). c.908G>A has been reported in the literature in homozygous individuals affected with Pyknodysostosis (Tora-Lopez_2011). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 21099701). ClinVar contains an entry for this variant (Variation ID: 2202838). Based on the evidence outlined above, the variant was classified as pathogenic.