Submissions for variant NM_198239.2(CCN6):c.296_298delinsTTA (p.Tyr99_Cys100delinsPheSer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324475	SCV004029836	pathogenic	Progressive pseudorheumatoid dysplasia	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: CCN6 c.296_298delinsTTA (p.Tyr99_Cys100delinsPheSer) results in an in-frame deletion-insertion that is predicted to cause changes in two amino acids in the insulin-like growth factor-binding protein domain (IPR000867) of the encoded protein sequence. In the literature, the variant is referred to as the constituent SNVs c.296A>T (p.Y99F) and c.298T>A (p.C100S). The variant as well as both of the constituent SNVs were absent in 250930 control chromosomes (gnomAD v2.1). c.296_298delinsTTA has been reported in the literature as the two constituent SNVs co-occurring in cis in at least four homozygous individuals affected with Progressive Pseudorheumatoid Dysplasia (e.g., Bhavani_2015, Sheth_2021). 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: 25988854, 34650595). No submitters have reported clinical-significance assessments for this variant or either of the constituent SNVs to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.