ClinVar Miner

Submissions for variant NM_000396.4(CTSK):c.136C>T (p.Arg46Trp)

gnomAD frequency: 0.00001  dbSNP: rs371277428
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669037 SCV000793735 likely pathogenic Pyknodysostosis 2017-08-29 criteria provided, single submitter clinical testing
Invitae RCV001071413 SCV001236717 pathogenic not provided 2023-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the CTSK protein (p.Arg46Trp). This variant is present in population databases (rs371277428, gnomAD 0.02%). This missense change has been observed in individuals with pycnodysostosis in a family and has also been observed to be homozygous in unrelated in individuals (PMID: 17206399, 24269275, 27092432). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553560). 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. 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001071413 SCV001480173 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669037 SCV003922650 pathogenic Pyknodysostosis 2023-03-03 criteria provided, single submitter clinical testing Variant summary: CTSK c.136C>T (p.Arg46Trp) results in a non-conservative amino acid change located in the Cathepsin propeptide inhibitor domain of 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 3.2e-05 in 249808 control chromosomes. c.136C>T has been reported in the literature in multiple individuals affected with Pyknodysostosis or osteopetrosis. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000669037 SCV004047335 likely pathogenic Pyknodysostosis criteria provided, single submitter clinical testing The missense variant c.136C>T (p.Arg46Trp) has been observed to segregate with pycnodysostosis in a family and has also been observed to be homozygous in unrelated in individuals (Pangrazio A et al., 2014). The p.Arg46Trp variant has been submitted allele frequency 0.003% in genomAD exomes and novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. The amino acid Arg at position 46 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg46Trp in CTSK is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab RCV000669037 SCV004049735 likely pathogenic Pyknodysostosis 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000669037 SCV004215249 pathogenic Pyknodysostosis 2023-07-07 criteria provided, single submitter clinical testing

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