ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.1412G>C (p.Gly471Ala) (rs779614415)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494214 SCV000581863 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing The G471A variant in the COL5A2 gene has not been published as pathogenic, nor has it been reported as benign to our knowledge. The G471A variant was not observed at any significant frequency across large population cohorts (Lek et al., 2016, 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the G471A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The G471A variant affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). However, in contrast to several other collagen genes, relatively few pathogenic Glycine substitutions have been reported in COL5A2 in association with Ehlers-Danlos syndrome. Most pathogenic variants in COL5A2 are in-frame splice site changes that cause exon skipping (Symoens et al., 2012). In addition, through whole exome sequencing, GeneDx has identified a Glycine substitution in a Gly-X-Y motif in the triple helical region of the COL5A2 gene that did not segregate with an EDS-like phenotype (GeneDx internal data).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000556708 SCV000631566 uncertain significance Ehlers-Danlos syndrome, classic type 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 471 of the COL5A2 protein (p.Gly471Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs779614415, ExAC 0.009%) but has not been reported in the literature in individuals with a COL5A2-related disease. 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), and missense variants at these glycine residues in COL5A2 are more frequently observed in individuals with disease than in the general population (PMID: 22696272, 23587214). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. 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. In summary, this variant is a rare missense change affecting a residue that is critical for protein structure, stability and function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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