ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3343G>C (p.Ala1115Pro) (rs748601646)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478936 SCV000572222 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. The A1115P variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The A1115P variant is asemi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ insome properties. In silico analysis predicts this variant is probably damaging to the protein structure/function.However, this substitution occurs at a position that is not conserved across species. Furthermore, the A1115P variantdoes not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where themajority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). However, in contrast toseveral other collagen genes, relatively few pathogenic Glycine substitutions have been reported in COL5A2 inassociation with Ehlers-Danlos syndrome. Most pathogenic variants in COL5A2 are in-frame splice site changes thatcause exon skipping (Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000707432 SCV000836530 uncertain significance Ehlers-Danlos syndrome, classic type 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 1115 of the COL5A2 protein (p.Ala1115Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs748601646, ExAC 0.005%). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 422696). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). 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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