ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3373G>A (p.Gly1125Arg) (rs151187317)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423732 SCV000522984 likely pathogenic not provided 2017-10-30 criteria provided, single submitter clinical testing The G1125R variant in the COL5A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency 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 G1125R 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, this substitution occurs at a position that is conserved across species, affecting a Glycine residue of the triple-helical region containing Gly-X-Y repeats, which represent the majority of pathogenic missense variants in the collagen genes associated with Ehlers-Danlos syndrome (Stenson et al., 2014; Symoens et al., 2012). We now interpret G1125R as a likely pathogenic variant. However, current information is not sufficient to definitively determine whether this variant is pathogenic or benign.
Invitae RCV000528400 SCV000631595 uncertain significance Ehlers-Danlos syndrome, classic type 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1125 of the COL5A2 protein (p.Gly1125Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs151187317, ExAC 0.006%). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 382848). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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