ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.2983C>A (p.Pro995Thr) (rs187022757)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485789 SCV000574085 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A1 gene. The P995T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P995T 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. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the P995T variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Invitae RCV000543992 SCV000631479 uncertain significance Ehlers-Danlos syndrome, classic type 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 995 of the COL5A1 protein (p.Pro995Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs187022757, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 424292). 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: "Tolerated"; 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.
Ambry Genetics RCV000620974 SCV000738600 uncertain significance Cardiovascular phenotype 2016-02-26 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence

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