Submissions for variant NM_001844.5(COL2A1):c.3589G>A (p.Gly1197Ser)

dbSNP: rs121912870

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000484896	SCV000339789	likely pathogenic	not provided	2016-03-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484896	SCV000568537	pathogenic	not provided	2023-06-12	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 (Jovanovic et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8423604, 34008892, 34007986, 33908178, 1905723, 15895462)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484896	SCV001581174	pathogenic	not provided	2023-06-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as 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). 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. ClinVar contains an entry for this variant (Variation ID: 17361). This variant is also known as Gly997Ser. This missense change has been observed in individual(s) with autosomal dominant spondyloepiphyseal dysplasia congenita or spondyloepimetaphyseal dysplasia (PMID: 1905723, 25604898, 26626311). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1197 of the COL2A1 protein (p.Gly1197Ser).
Blueprint Genetics	RCV000484896	SCV001832309	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729352	SCV001976703	pathogenic	Spondyloepimetaphyseal dysplasia, Strudwick type	2021-10-01	criteria provided, single submitter	clinical testing	PS1, PM1, PM2, PP2, PP3, PP5
Revvity Omics, Revvity	RCV000484896	SCV002017449	pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing
Mendelics	RCV002247358	SCV002516270	likely pathogenic	Stickler syndrome type 1	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272023	SCV002557613	pathogenic	Namaqualand hip dysplasia	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. Intra- and inter-familial phenotypic variability and expressivity has been reported (GeneReviews). (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 and highly conserved with a minor amino acid change. (SP) 0601 - Variant is located in the well-established functional collagen triple helical domain. The variant affects the glycine of the Gly-X-Y repeat in this domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals with spondyloepiphyseal dysplasia or spondyloepiphyseal dysplasia congenita (ClinVar, PMIDs: 15895462, 25604898). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276564	SCV002566365	pathogenic	Connective tissue disorder	2020-02-01	criteria provided, single submitter	clinical testing
3billion	RCV003152666	SCV003841593	pathogenic	Spondyloperipheral dysplasia	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017361). Different missense changes at the same codon (p.Gly1197Ala, p.Gly1197Arg) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000988359, VCV001326882). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV003320353	SCV004024491	pathogenic	Type 2 collagenopathy	2023-07-01	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV000018905	SCV004047513	pathogenic	Spondyloepiphyseal dysplasia congenita		criteria provided, single submitter	clinical testing	The missense variant c.3589G>A (p.Gly1197Ser) in COL2A1 gene has been reported in heterozygous state in in individual(s) with autosomal dominant spondyloepiphyseal dysplasia congenita or spondyloepimetaphyseal dysplasia (Barat-Houari et al.). Experimental studies have shown that this missense 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 (Shoulders MD, Raines RT). The p.Gly1197Ser variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic.The amino acid Gly at position 1197 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly1197Ser in COL2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV002247358	SCV004101514	pathogenic	Stickler syndrome type 1		criteria provided, single submitter	clinical testing	The COL2A1 c.3589G>A (p.Gly1197Ser) variant has been reported in heterozygous state in affected individuals. 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. This variant is novel (not in any individual) in the gnomad and in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Gly at position 1197 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gly1197Ser in COL2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000018905	SCV000039189	pathogenic	Spondyloepiphyseal dysplasia congenita	1993-01-01	no assertion criteria provided	literature only