Submissions for variant NM_001844.5(COL2A1):c.192C>A (p.Cys64Ter)

dbSNP: rs121912897

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657640	SCV000779385	pathogenic	not provided	2018-11-20	criteria provided, single submitter	clinical testing	The C64X variant in the COL2A1 gene has been reported previously in individuals with a predominantly ocular form of Stickler syndrome characterized by myopia and retinal detachment with cataract, perivascular pigmentation, and peripapillary retinal pigmentary atrophy reported in some individuals (McAlinden et al., 2008; Edwards et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The C64X variant is not observed in large population cohorts (Lek et al., 2016). We interpret C64X as a pathogenic variant.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470714	SCV002767220	pathogenic	Stickler syndrome type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Missense variants affecting glycine residue exert dominant-negative effect and is commonly associated with spondyloepiphyseal dysplasia (SED) (PMID: 15895462). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both inter and intra-familial variability have been reported (GeneReviews). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Although this variant does not lie within a splice region, minigene assays have demonstrated skipping of exon 2 (PMID: 17721977). However, nonsense-mediated decay has not been excluded. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least five unrelated probands with Sticker syndrome (MIM#108300), including a large family with eighteen affected individuals. In addition, this variant has been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 17721977, 20513134, 22574936). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657640	SCV003440519	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 17401). This premature translational stop signal has been observed in individual(s) with clinical features of Stickler syndrome (PMID: 17721977). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys64*) in the COL2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744).
OMIM	RCV000018945	SCV000039231	pathogenic	Stickler syndrome, type I, nonsyndromic ocular	2008-01-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657640	SCV001741130	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000657640	SCV001952113	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532390	SCV004714916	pathogenic	COL2A1-related disorder	2023-12-21	no assertion criteria provided	clinical testing	The COL2A1 c.192C>A variant is predicted to result in premature protein termination (p.Cys64*). This variant has been reported in two unrelated individual with Stickler syndrome who displayed only the ocular phenotypes (McAlinden et al. 2008. PubMed ID: 17721977). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Nonsense variants in COL2A1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.