ClinVar Miner

Submissions for variant NM_000396.4(CTSK):c.26T>C (p.Leu9Pro)

dbSNP: rs1057517252
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409305 SCV000486985 likely pathogenic Pyknodysostosis 2016-09-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000409305 SCV004215256 likely pathogenic Pyknodysostosis 2023-03-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003558364 SCV004292001 likely pathogenic not provided 2023-08-23 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 371412). This missense change has been observed in individuals with pycnodysostosis (PMID: 10571690, 10634420). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 9 of the CTSK protein (p.Leu9Pro). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change alters CTSK gene expression (PMID: 10634420).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409305 SCV005077600 likely pathogenic Pyknodysostosis 2024-04-18 criteria provided, single submitter clinical testing Variant summary: CTSK c.26T>C (p.Leu9Pro) results in a non-conservative amino acid change located in the pre-region critical for transfer of the nascent protein to the endoplasmic reticulum (Nishi_1999). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251324 control chromosomes. c.26T>C has been reported in the literature as a biallelic genotype in individuals affected with Pyknodysostosis (example, Nishi_1999, Bae_2016). These data indicate that the variant is 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: 26402641, 17397052, 10571690, 25550899). ClinVar contains an entry for this variant (Variation ID: 371412). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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