ClinVar Miner

Submissions for variant NM_001854.4(COL11A1):c.4538G>A (p.Gly1513Asp)

dbSNP: rs1553193913
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523421 SCV000617761 likely pathogenic not provided 2017-08-10 criteria provided, single submitter clinical testing The G1513D variant in the COL11A1 gene been reported previously in an individual with Stickler syndrome (Richards et al., 2010). The G1513D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G1513D 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, affecting a Glycine residue in the Gly-X-Y repetitive motif of the triple helical region of the COL11A1 gene. In this domain, the Glycine in the triplet repeat is critical for protein folding and substitution of a triplet Glycine is a known pathogenic mechanism (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby Glycine residues (G1507D, G1516V) have been reported in the Human Gene Mutation Database in association with COL11A1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G1513D as a likely pathogenic variant.
Invitae RCV000523421 SCV002289209 likely pathogenic not provided 2021-04-03 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 COL11A1 protein function. This variant has been observed in individual(s) with Stickler syndrome (PMID: 20513134, Invitae). This variant is also known as c.4574G>A. ClinVar contains an entry for this variant (Variation ID: 449528). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 1513 of the COL11A1 protein (p.Gly1513Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.

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