Submissions for variant NM_001844.5(COL2A1):c.2167G>A (p.Gly723Ser)

dbSNP: rs1939173389

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion, Medical Genetics	RCV001775391	SCV002012244	likely pathogenic	Spondyloepimetaphyseal dysplasia, Strudwick type	2021-10-02	criteria provided, single submitter	clinical testing	The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.995, 3Cnet: 0.967, PP3). This variant is sharted with the similarly affected sibling and their phenotype is considered compatible with COL2A1-related skeletal dysplasia. (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002034501	SCV002275554	likely pathogenic	not provided	2021-10-20	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL2A1 protein function. 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. This variant disrupts the triple helix domain of COL2A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL2A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with COL2A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, a(n) neutral and non-polar amino acid, with serine, a(n) neutral and polar amino acid, at codon 723 of the COL2A1 protein (p.Gly723Ser).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594588	SCV005086481	likely pathogenic	Type 2 collagenopathy	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL2A1-related disorders. Loss of function variants have been reported to cause Stickler syndrome, whereas missense variants with a dominant negative effect on protein function result in spondyloepiphyseal or spondyloepimetaphyseal dysplasia (OMIM, PMIDs: 35052477, 15895462). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301479). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif within the collagen repeat motif, and affects a glycine residue (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly723Asp) has been classified as likely pathogenic by a clinical laboratory in ClinVar. (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by two clinical laboratories in ClinVar, one of whom observed this variant in two siblings with COL2A1-related skeletal dysplasia. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign