NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr) AND Pyknodysostosis

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Dec 13, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001830739.6

Allele description [Variation Report for NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr)]

NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr)

Gene:

CTSK:cathepsin K [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

NM_000396.4(CTSK):c.953G>A (p.Cys318Tyr)

HGVS:

NC_000001.11:g.150796836C>T
NG_011848.1:g.16501G>A
NM_000396.4:c.953G>AMANE SELECT
NP_000387.1:p.Cys318Tyr
NC_000001.10:g.150769312C>T
NM_000396.3:c.953G>A

Protein change:

C318Y

Links:

dbSNP: rs762780994

NCBI 1000 Genomes Browser:

rs762780994

Molecular consequence:

NM_000396.4:c.953G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pyknodysostosis
Synonyms:: Pycnodysostosis
Identifiers:: MONDO: MONDO:0009940; MedGen: C0238402; Orphanet: 763; OMIM: 265800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002085803	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 17, 2021)	germline	clinical testing
SCV002810479	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004034097	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004049709	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004215236	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004241044	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20814951, 31680459 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Craniosynostosis in pycnodysostosis: broadening the spectrum of the cranial flat bone abnormalities.

Bertola D, Amaral C, Kim C, Albano L, Aguena M, Passos-Bueno MR.

Am J Med Genet A. 2010 Oct;152A(10):2599-603. doi: 10.1002/ajmg.a.33609.

PubMed [citation]

PMID:: 20814951

See all PubMed Citations (3)

Details of each submission

From Natera, Inc., SCV002085803.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002810479.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV004034097.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004049709.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004215236.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241044.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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