ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.266C>T (p.Pro89Leu) (rs139610730)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252928 SCV000319269 uncertain significance Cardiovascular phenotype 2014-05-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000494585 SCV000583216 uncertain significance not specified 2017-05-03 criteria provided, single submitter clinical testing The P98L variant of uncertain significance in the COL3A1 gene has not been published as pathogenic or been reported as benign to our knowledge. P98L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the P98L variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Furthermore, the P98L variant was observed in 6/66,112 alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016).
Invitae RCV000553256 SCV000631646 uncertain significance Ehlers-Danlos syndrome, type 4 2018-09-22 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 89 of the COL3A1 protein (p.Pro89Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs139610730, ExAC 0.009%) but has not been reported in the literature in individuals with a COL3A1-related disease. ClinVar contains an entry for this variant (Variation ID: 263835). 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, this variant is a rare  missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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