ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys) (rs121912884)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413561 SCV000491206 likely pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The R565C variant in the COL2A1 gene has been previously reported in several individuals with Stickler syndrome (Richards et al., 2000; Hoornaert et al., 2010; Wang et al., 2016; Richards et al., 2010). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R565C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R565C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000413561 SCV001228620 pathogenic not provided 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 565 of the COL2A1 protein (p.Arg565Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Stickler syndrome or early onset high myopia (PMID: 11007540, 27390512, 26747767, 29453956). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17383). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Clinical Services Laboratory,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.
OMIM RCV000018926 SCV000039211 pathogenic Stickler syndrome type 1 2000-11-01 no assertion criteria provided literature only

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