Variant summary: CTSK c.953G>A (p.Cys318Tyr) results in a non-conservative amino acid change located in the Peptidase C1A, papain C-terminal domain (IPR000668) 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 1.2e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.953G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Pyknodysostosis (e.g., Bertola_2010, Khirani_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20814951, 31680459). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr)
Variation ID: 649051 Accession: VCV000649051.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.3 1: 150796836 (GRCh38) [ NCBI UCSC ] 1: 150769312 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 14, 2019 Jun 23, 2024 Mar 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000396.4:c.953G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000387.1:p.Cys318Tyr missense NC_000001.11:g.150796836C>T NC_000001.10:g.150769312C>T NG_011848.1:g.16501G>A - Protein change
- C318Y
- Other names
- -
- Canonical SPDI
- NC_000001.11:150796835:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CTSK | - | - |
GRCh38 GRCh37 |
381 | 393 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000803909.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001814239.1 | |
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 5, 2024 | RCV001830739.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the skeletal system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755239.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
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Pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810479.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: research
|
Pyknodysostosis
Affected status: yes
Allele origin:
germline
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004034097.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
|
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Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004049709.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
|
Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241044.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: CTSK c.953G>A (p.Cys318Tyr) results in a non-conservative amino acid change located in the Peptidase C1A, papain C-terminal domain (IPR000668) of the encoded protein … (more)
Variant summary: CTSK c.953G>A (p.Cys318Tyr) results in a non-conservative amino acid change located in the Peptidase C1A, papain C-terminal domain (IPR000668) 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 1.2e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.953G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Pyknodysostosis (e.g., Bertola_2010, Khirani_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20814951, 31680459). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000943797.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 318 of the CTSK protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 318 of the CTSK protein (p.Cys318Tyr). This variant is present in population databases (rs762780994, gnomAD 0.02%). This missense change has been observed in individual(s) with pycnodysostosis (PMID: 20814951, 24057333, 27558267). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 649051). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215236.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Feb 17, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085803.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Pyknodysostosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Dr.Nikuei Genetic Center
Accession: SCV005061488.1
First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024 |
|
Comment:
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 318 of the CTSK protein (p.Cys318Tyr). This variant is present in population databases (rs762780994, gnomAD 0.02%). This missense change has been observed in individual(s) with pycnodysostosis (PMID: 20814951, 24057333, 27558267). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 649051). 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%. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: CTSK c.953G>A (p.Cys318Tyr) results in a non-conservative amino acid change located in the Peptidase C1A, papain C-terminal domain (IPR000668) 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 1.2e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.953G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Pyknodysostosis (e.g., Bertola_2010, Khirani_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20814951, 31680459). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 318 of the CTSK protein (p.Cys318Tyr). This variant is present in population databases (rs762780994, gnomAD 0.02%). This missense change has been observed in individual(s) with pycnodysostosis (PMID: 20814951, 24057333, 27558267). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 649051). 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%. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sleep-disordered breathing in children with pycnodysostosis. | Khirani S | American journal of medical genetics. Part A | 2020 | PMID: 31680459 |
| Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region. | Araujo TF | European journal of medical research | 2016 | PMID: 27558267 |
| Pycnodysostosis with novel gene mutation and severe obstructive sleep apnoea: management of a complex case. | Girbal I | BMJ case reports | 2013 | PMID: 24057333 |
| Craniosynostosis in pycnodysostosis: broadening the spectrum of the cranial flat bone abnormalities. | Bertola D | American journal of medical genetics. Part A | 2010 | PMID: 20814951 |
Text-mined citations for rs762780994 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.