ClinVar Genomic variation as it relates to human health

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP3.

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.

This sequence change creates a premature translational stop signal (p.Cys52*) in the WISP3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WISP3 are known to be pathogenic (PMID: 22791401). This variant is present in population databases (rs121908901, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with progressive pseudorheumatoid dysplasia (PMID: 10471507, 16152649, 27291587, 29092958). ClinVar contains an entry for this variant (Variation ID: 6381). For these reasons, this variant has been classified as Pathogenic.

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

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).

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.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21528827, 25525159, 10471507, 16152649, 27291587, 29092958, 34650595, 27436824, 34919662, 34430442)