Submissions for variant NM_000396.4(CTSK):c.150G>A (p.Trp50Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003575112	SCV004335382	pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp50*) in the CTSK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTSK are known to be pathogenic (PMID: 12125807, 21569238). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CTSK-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical and Molecular Genetics, The National Medical Research Center for Endocrinology	RCV003485990	SCV004232443	likely pathogenic	Pyknodysostosis	2024-01-19	no assertion criteria provided	clinical testing	The c.150G>A (exon 3 of 8) variant in the cathepsin K gene, CTSK, results in a premature termination at codon 50 p.(Trp50Ter) of NM_000396.4. The loss of function in a gene CTSK is an established disease mechanism (PVS1; PMID: 8938428). This variant is absent in gnomAD v2.1.1, v3.1.2, v4.0.0 (PM2_Supporting). This variant was identified in an individual with a clinical history consistent with pycnodysostosis (short stature, persistent open anterior and posterior fontanelles, sagittal and lambdoid sutures, acroosteolysis of the distal phalanges of the hands, spontaneous fractures). Taken together, this evidence supports the classification of this variant as likely pathogenic for This variant was identified in an individual with a clinical history consistent with pycnodysostosis. ACMG/AMP criteria applied: PVS1, PM2_Supporting.