NM_198239.2(CCN6):c.156C>A (p.Cys52Ter) AND Progressive pseudorheumatoid dysplasia

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Jul 10, 2024
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:: RCV000006753.21

Allele description [Variation Report for NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)]

NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)

Gene:

CCN6:cellular communication network factor 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q21

Genomic location:

Preferred name:

NM_198239.2(CCN6):c.156C>A (p.Cys52Ter)

HGVS:

NC_000006.12:g.112061098C>A
NG_011748.1:g.12024C>A
NM_003880.4:c.156C>A
NM_198239.2:c.156C>AMANE SELECT
NP_003871.1:p.Cys52Ter
NP_003871.1:p.Cys52Ter
NP_937882.1:p.Cys70Ter
NP_937882.2:p.Cys52Ter
NC_000006.11:g.112382301C>A
NM_003880.3:c.156C>A
NM_198239.1:c.210C>A
NR_125353.2:n.410C>A
NR_125354.3:n.237C>A

Protein change:

C52*; CYS52TER

Links:

OMIM: 603400.0003; dbSNP: rs121908901

NCBI 1000 Genomes Browser:

rs121908901

Molecular consequence:

NR_125353.2:n.410C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_125354.3:n.237C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_003880.4:c.156C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_198239.2:c.156C>A - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Name:: Progressive pseudorheumatoid dysplasia (PPRD)
Synonyms:: SPONDYLOEPIPHYSEAL DYSPLASIA TARDA WITH PROGRESSIVE ARTHROPATHY; Progressive Pseudorheumatoid Arthropathy of Childhood
Identifiers:: MONDO: MONDO:0008827; MedGen: C0432215; Orphanet: 1159; OMIM: 208230

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026945	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000607728	Snyder Lab, Genetics Department, Stanford University	no assertion criteria provided	Pathogenic	inherited	research
SCV000930108	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 27, 2019)	unknown	curation	PubMed (6) [See all records that cite these PMIDs] 10471507, 22987568, 25988854, 29092958, 16152649, 25741868
SCV002020909	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002521000	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002571753	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29092958, 30408610 Citation Link,
SCV002767046	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 26, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22791401, 29092958, 25741868
SCV004810099	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005200349	Dr.Nikuei Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005442684	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.

Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML.

Nat Genet. 1999 Sep;23(1):94-8.

PubMed [citation]

PMID:: 10471507

Analysis of the WISP3 gene in Indian families with progressive pseudorheumatoid dysplasia.

Dalal A, Bhavani G SL, Togarrati PP, Bierhals T, Nandineni MR, Danda S, Danda D, Shah H, Vijayan S, Gowrishankar K, Phadke SR, Bidchol AM, Rao AP, Nampoothiri S, Kutsche K, Girisha KM.

Am J Med Genet A. 2012 Nov;158A(11):2820-8. doi: 10.1002/ajmg.a.35620. Epub 2012 Sep 17.

PubMed [citation]

PMID:: 22987568

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000026945.4

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

Description

In a French family with progressive pseudorheumatoid arthropathy (PPRD; 208230), Hurvitz et al. (1999) found compound heterozygosity for a C-to-A transversion at nucleotide 156 of the CCN6 gene, resulting in a cys52-to-ter (C52X) substitution, and a T-to-C transition at nucleotide 232 of the WISP3 gene, resulting in a cys78-to-arg substitution (C78R; 603400.0004).

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

From Snyder Lab, Genetics Department, Stanford University, SCV000607728.2

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

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

From SIB Swiss Institute of Bioinformatics, SCV000930108.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

This variant is interpreted as a Pathogenic for Progressive pseudorheumatoid arthropathy of childhood, autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1-Moderate : PP1 upgraded in strength to Moderate (PMID:29092958). PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Very strong : PM3 upgraded in strength to Very Strong (PMID:10471507; 22987568; 25988854; 29092958; 16152649).

#	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 Revvity Omics, Revvity, SCV002020909.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002521000.1

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

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000006381). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002571753.1

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

Description

Variant summary: CCN6 (also known as WISP3) c.156C>A (p.Cys52X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.9e-05 in 282674 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CCN6 causing Progressive Pseudorheumatoid Dysplasia (3.9e-05 vs 0.0011), allowing no conclusion about variant significance. c.156C>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Progressive Pseudorheumatoid Dysplasia (Sailani_2018, Uttarilli_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as 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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767046.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 3 of 6). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple variants predicted to cause NMD have been reported in individuals with progressive pseudorheumatoid arthropathy (ClinVar; Garcia Segarra, N., et al. (2012)) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple patients (ClinVar, Sailani, M., et al. (2018); Garcia Segarra, N., et al. (2012)) (P) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	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 Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004810099.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Dr.Nikuei Genetic Center, SCV005200349.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005442684.1

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

Description

The observed stop gain c.156C>A p.Cys52Ter variant in CCN6 gene has been previously reported in compound heterozygous state in multiple individuals affected with progressive pseudorheumatoid dysplasia Sheth H et al. 2021; Hurvitz JR et al. 1999. The p.Cys52Ter variant has allele frequency 0.004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submitters. Computational evidence Mutation Taster - Disease causing predicts damaging effect on protein structure and function for this variant. The reference nucleotide change c.156C>A on CCN6 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in WISP3 are known to be pathogenic Garcia Segarra N et al. 2012. For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: May 16, 2025

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