Submissions for variant NM_001844.5(COL2A1):c.2005G>A (p.Gly669Ser)

dbSNP: rs1939205327

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001095762	SCV001251605	likely pathogenic	COL2A1-related disorders	2020-02-12	criteria provided, single submitter	clinical testing	The COL2A1 c.2005G>A (p.Gly669Ser) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. The p.Gly669Ser variant results in a glycine residue change in the triple-helical region of the gene, an established cause of disease in COL2A1-related disorders (Barat-Houari et al. 2016). The Gly-X-Y backbone of the protein is critical to folding and stability and substitutions of glycine account for a high percentage of disease-causing variants in COL2A1 collagenopathies (Barat-Houari et al. 2016; Deng et al. 2016). Based on its detection in a de novo state, its location in an important region, and its rarity, the p.Gly669Ser variant is classified as likely pathogenic for COL2A1-related disorders.
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	RCV001787123	SCV002029105	pathogenic	Spondyloepiphyseal dysplasia congenita	2018-06-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276622	SCV002567211	pathogenic	Connective tissue disorder	2021-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV002555977	SCV003224869	likely pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 669 of the COL2A1 protein (p.Gly669Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spondyloepiphyseal dysplasia congenita (PMID: 35052477). ClinVar contains an entry for this variant (Variation ID: 873513). 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 with a positive predictive value of 95%. 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). 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.