ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3268C>T (p.Pro1090Ser) (rs761543775)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199716 SCV000249978 uncertain significance not provided 2016-10-18 criteria provided, single submitter clinical testing TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011). p.Pro1090Ser (CCT>TCT): c.3268 C>T in exon 46 of the COL5A2 gene (NM_000393.3)The Pro1090Ser variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Pro1090Ser variant was not observed 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. Pro1090Ser results in a non-conservative amino acid substitution of a non-polar, sterically constrained Proline with a polar Serine at a position in the triple helix region that is well conserved across species. Consequently, in silico analysis predicts Pro1090Ser is damaging to the protein structure/function. However, mutations in nearby residues have not been reported, and missense mutations in the triple helix region almost invariable involve substitution of a Glycine residue (Malfait F et al., 2011).With the clinical and molecular information available at this time, we cannot definitively determine if Pro1090Ser is a disease-causing mutation or a rare benign variant. This variant was found in TAAD.
Invitae RCV000467613 SCV000547871 uncertain significance Ehlers-Danlos syndrome, classic type 2016-06-08 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1090 of the COL5A2 protein (p.Pro1090Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs761543775, ExAC 0.01%) but has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213115). 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 with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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