Submissions for variant NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys)

dbSNP: rs121912884

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413561	SCV000491206	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); Other missense variants that introduce a cysteine residue in the triple helical domain have been reported in association with COL2A1-related conditions (HGMD); This variant is associated with the following publications: (PMID: 26443184, 18309338, 32039712, 11007540, 20179744, 27390512, 21204228, 16155195, 20513134, 16752401, 28283280, 30181686, 29453956, 26747767, 31758797, 32112773, 30653986, 32756486, 34737199, 34680973, 24077912, 35473494)
Invitae	RCV000413561	SCV001228620	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 565 of the COL2A1 protein (p.Arg565Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stickler syndrome or early onset high myopia (PMID: 11007540, 26747767, 27390512, 29453956). In at least one individual the variant was observed to be de novo. This variant is also known as R365C. ClinVar contains an entry for this variant (Variation ID: 17383). 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 not expected to disrupt COL2A1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074673	SCV001240266	likely pathogenic	Retinal dystrophy	2019-03-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095763	SCV001251606	pathogenic	COL2A1-related disorders	2020-02-06	criteria provided, single submitter	clinical testing	The COL2A1 c.1693C>T (p.Arg565Cys) variant is a missense variant that has a well-documented association with Stickler syndrome. Across a selection of the available literature, this variant has been reported in a heterozygous state in at least eight affected individuals, including in a de novo state in one individual with confirmed parentage (Richards et al. 2000; Hoornaert et al. 2000; Wang et al. 2016; Zhou et al. 2018). This variant is not reported in the Genome Aggegation Database in a region of good sequencing coverage, indicating it is rare. The variant results in the substitution of a cysteine for an arginine in the X position of the Gly-X-Y repeat of the triple helical domain; this type of variant has been linked to ocular phenotypes. In addition to vitreous anomalies, myopia, and other ophthalmological anomalies, carriers of the p.Arg565Cys variant showed midface flattening, prominent eyes, low nasal bridge, and micrognathia. Mosaicism has been previously reported for COL2A1-related Stickler syndrome (Nagendran et al. 2012; Stevenson et al. 2012). Based on the cumulative evidence, the p.Arg565Cys variant is classified as pathogenic for COL2A1-related disorders.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197973	SCV001368758	likely pathogenic	Achondrogenesis type II	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP4,PP5.
3billion	RCV001807733	SCV002058505	pathogenic	Stickler syndrome, type I, nonsyndromic ocular	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 26747767, 27390512, 27390512, PS2_S). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 26747767, 27390512, 27390512, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.687, 3CNET: 0.905, PP3_P). A missense variant is a common mechanism associated with Stickler sydrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000018926	SCV002556604	likely pathogenic	Stickler syndrome type 1	2021-12-22	criteria provided, single submitter	clinical testing
Center of Medical Genetics, Central South University	RCV000018926	SCV002576563	likely pathogenic	Stickler syndrome type 1	2022-07-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018926	SCV002766637	pathogenic	Stickler syndrome type 1	2022-03-31	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. Loss of function is associated with Stickler Syndrome while missense variants affecting glycine residue exert dominant-negative effect and is commonly associated with spondyloepiphyseal dysplasia (PMIDs: 15895462, 27234559). (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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 16 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated triple-helical region (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Stickler (ClinVar, PMIDs: 16752401, 20179744). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000018926	SCV000039211	pathogenic	Stickler syndrome type 1	2000-11-01	no assertion criteria provided	literature only