Submissions for variant NM_198239.2(CCN6):c.49-1G>A

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003555298	SCV004294657	likely pathogenic	not provided	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the WISP3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in WISP3 are known to be pathogenic (PMID: 22791401). This variant is present in population databases (rs781864926, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with progressive pseudorheumatoid dysplasia (PMID: 25988854). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV004821336	SCV005442683	likely pathogenic	Progressive pseudorheumatoid dysplasia	2023-07-22	criteria provided, single submitter	clinical testing	The invariant splice acceptor c.49-1G>A in CCN6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.49-1G>A variant has allele frequency 0.001% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. SpliceAI predicts this variant to cause splice acceptor gain score-0.06. Loss of function variants have been previously reported to be disease causing. Functional studies are required to prove the pathogenicity for the variant, For these reasons, this variant has been classified as Likely Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV004821336	SCV005894726	pathogenic	Progressive pseudorheumatoid dysplasia	2025-02-25	criteria provided, single submitter	clinical testing	A homozygous missense variant in intron 1 of the CCN6. The observed variant c.49-1G>A (p.?) has a minor allele frequency of 0.012% and 0.009% in the ExAC and gnomAD databases, respectively. The in-silico prediction of the variant are possibly damaging by FATHMM, DANN, CADD and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.