ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.3589G>A (p.Gly1197Ser) (rs121912870)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000484896 SCV000339789 likely pathogenic not provided 2016-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000484896 SCV000568537 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing The G1197S variant in the COL2A1 gene has been reported previously, sometimes using alternate nomenclature G997S, in multiple individuals with spondyloepiphyseal dysplasia congenita (Chan et al., 1991; Nishimura et al., 2005). The G1197S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G1197S variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species, affecting a Glycine residue of the triple-helical region containing Gly-X-Y repeats. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants affecting nearby glycine residues within a G-X-Y motif (G1200S, G1200C) have been reported in the Human Gene Mutation Database in association with COL2A1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret G1197S as a pathogenic variant
Invitae RCV000484896 SCV001581174 pathogenic not provided 2020-02-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1197 of the COL2A1 protein (p.Gly1197Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant 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 also known as Gly997Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 17361). 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 10612821, 26443184) compared to the general population (ExAC). 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

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