Submissions for variant NM_001844.5(COL2A1):c.1527+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472045	SCV002768401	likely pathogenic	Stickler syndrome, type I, nonsyndromic ocular	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. Premature termination codon variants result in haploinsufficiency and have previously been reported pathogenic in Stickler Syndrome (PMID: 20179744; ClinVar). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Missense variants affecting glycine residues within the repeat region result in aberrant disulphide bond formation and a dominant negative effect. (PMID: 15895462). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0508 - In silico predictions for abnormal splicing are conflicting. (N) 0702 - Comparable variants have strong previous evidence for pathogenicity. Other variants in the same splice region (c.1527+1G>T and c.1527+4A>T) have been reported in patients with Stickler syndrome (PMID: 27408751, 26443184). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV005098458	SCV005759789	likely pathogenic	not provided	2024-06-29	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 23 of the COL2A1 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 COL2A1 are known to be pathogenic (PMID: 20179744). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Stickler syndrome (PMID: 26443184). ClinVar contains an entry for this variant (Variation ID: 1805627). 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.