This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 146 of the CTSK protein (p.Gly146Arg). This variant is present in population databases (rs74315302, gnomAD 0.01%). This missense change has been observed in individuals with pycnodysostosis (PMID: 8703060, 20044043, 27558267). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8421). 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: 10074491). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000396.4(CTSK):c.436G>C (p.Gly146Arg)
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.
(7)
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
7
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.436G>C (p.Gly146Arg)
Variation ID: 8421 Accession: VCV000008421.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q21.3 1: 150804203 (GRCh38) [ NCBI UCSC ] 1: 150776679 (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 Apr 4, 2013 Jun 17, 2024 Feb 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000396.4:c.436G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000387.1:p.Gly146Arg missense NC_000001.11:g.150804203C>G NC_000001.10:g.150776679C>G NG_011848.1:g.9134G>C P43235:p.Gly146Arg - Protein change
- G146R
- Other names
- -
- Canonical SPDI
- NC_000001.11:150804202:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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 |
382 | 394 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 4, 2024 | RCV000008932.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 23, 2017 | RCV000623420.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 23, 2023 | RCV001206530.6 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002796189.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004049728.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
|
Pathogenic
(Dec 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001377841.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 146 of the CTSK protein (p.Gly146Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 146 of the CTSK protein (p.Gly146Arg). This variant is present in population databases (rs74315302, gnomAD 0.01%). This missense change has been observed in individuals with pycnodysostosis (PMID: 8703060, 20044043, 27558267). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8421). 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: 10074491). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215254.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742962.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Asian/Filipino/Caucasian/German/Irish/Welsh/Hispanic/Mexican
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Obstructive sleep apnea syndrome (present) , Skeletal dysplasia (present) , Scoliosis (present) , Short stature (present) , Dolichocephaly (present) , Narrow forehead (present) , Frontal … (more)
Obstructive sleep apnea syndrome (present) , Skeletal dysplasia (present) , Scoliosis (present) , Short stature (present) , Dolichocephaly (present) , Narrow forehead (present) , Frontal bossing (present) , Blue sclerae (present) , Proptosis (present) , Dental crowding (present) , High palate (present) , Brachydactyly (present) , Short phalanx of finger (present) , Proximal placement of thumb (present) , Clubbing of fingers (present) , Pes planus (present) , Bulbous tips of toes (present) , Sandal gap (present) , Abnormality of the ribs (present) , Abnormality of the mandible (present) , Midface retrusion (present) , Abnormality of the maxilla (present) , Abnormality of facial skeleton (present) , Abnormality of fontanelles (present) , Persistent open anterior fontanelle (present) , Abnormality of the tonsils (present) , Wormian bones (present) , Parietal bossing (present) , Thin calvarium (present) , Absent/hypoplastic paranasal sinuses (present) , Increased bone mineral density (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
|
|
|
Pathogenic
(Aug 30, 1996)
|
no assertion criteria provided
Method: literature only
|
PYCNODYSOSTOSIS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029142.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 Moroccan Arab sibs with pycnodysostosis (265800), Gelb et al. (1996) demonstrated a missense mutation, a G-to-C transversion at nucleotide 541, predicting a gly146-to-arg … (more)
In 2 Moroccan Arab sibs with pycnodysostosis (265800), Gelb et al. (1996) demonstrated a missense mutation, a G-to-C transversion at nucleotide 541, predicting a gly146-to-arg (G146R) substitution. (less)
|
|
|
Pathogenic
(Jul 21, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Pyknodysostosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085806.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
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:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 146 of the CTSK protein (p.Gly146Arg). This variant is present in population databases (rs74315302, gnomAD 0.01%). This missense change has been observed in individuals with pycnodysostosis (PMID: 8703060, 20044043, 27558267). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8421). 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: 10074491). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect. | Otaify GA | Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA | 2018 | PMID: 29796728 |
| 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 |
| Craniosynostosis in pycnodysostosis: broadening the spectrum of the cranial flat bone abnormalities. | Bertola D | American journal of medical genetics. Part A | 2010 | PMID: 20814951 |
| Craniosynostosis: A rare complication of pycnodysostosis. | Osimani S | European journal of medical genetics | 2010 | PMID: 20044043 |
| Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Online. | Donnarumma M | Human mutation | 2007 | PMID: 17397052 |
| Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. | Hou WS | The Journal of clinical investigation | 1999 | PMID: 10074491 |
| Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. | Gelb BD | American journal of human genetics | 1998 | PMID: 9529353 |
| Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. | Gelb BD | Science (New York, N.Y.) | 1996 | PMID: 8703060 |
Text-mined citations for rs74315302 ...
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.