Submissions for variant NM_001844.5(COL2A1):c.655G>A (p.Gly219Arg)

dbSNP: rs1131691822

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494511	SCV000582924	pathogenic	not provided	2020-01-14	criteria provided, single submitter	clinical testing	Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31827275)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089571	SCV001244776	pathogenic	Stickler syndrome type 1	2018-08-06	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_001844.4(COL2A1):c.655G>A, has been identified in exon 10 of 54 of the COL2A1 gene. The variant is predicted to result in a major amino acid change from glycine to arginine at position 219 of the protein (NP_001835.3(COL2A1):p.(Gly219Arg)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the triple-helical region. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in several patients with Stickler syndrome (Hoornaert K. et al. (2010), ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
PreventionGenetics, part of Exact Sciences	RCV004527601	SCV004110120	pathogenic	COL2A1-related disorder	2023-05-30	criteria provided, single submitter	clinical testing	The COL2A1 c.655G>A variant is predicted to result in the amino acid substitution p.Gly219Arg. The p.Gly219Arg variant was reported in an individual with hearing loss, myopia and dysmorphism and another individual with Stickler syndrome (Table 3, Downie et al 2020. PubMed ID: 31827275; Table 1, Hoornaert. 2010. PubMed ID: 20179744 ). A different variant affecting the same amino acid (p.Gly219Glu) was reported to be pathogenic for Stickler syndrome (Table S1, Barat-Houari. 2016. PubMed ID: 26443184). The p.Gly219 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Barat-Houari et al. 2016. PubMed ID: 26626311; Markova et al. 2022. PubMed ID: 35052477). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.