ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.3490G>A (p.Gly1164Ser)

dbSNP: rs2136514646
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001382420 SCV001581177 pathogenic not provided 2022-10-28 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 1070315). This missense change has been observed in individuals with spondyloepiphyseal dysplasia congenita and spondyloepimetaphyseal dysplasia, Strudwick type (PMID: 22791362; Invitae). 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 1164 of the COL2A1 protein (p.Gly1164Ser).
Mendelics RCV002246366 SCV002518743 pathogenic Stickler syndrome type 1 2022-05-04 criteria provided, single submitter clinical testing
GeneDx RCV001382420 SCV005201921 pathogenic not provided 2023-05-15 criteria provided, single submitter clinical testing Identified in a patient with spondyloepimetaphyseal dysplasia Strudwick type in published literature (Terhal et al., 2012); Occurs in the triple helical domain and replaces a glycine in a 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: 34007986, 22791362)

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