ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.472T>A (p.Tyr158Asn) (rs756125442)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769562 SCV000900959 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000523264 SCV000617121 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. The Y158N 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 Y158N variant 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 across species, and in silico analysis suggests that this variant is probably damaging to the protein structure/function. However, the Y158N 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).
Invitae RCV000634714 SCV000756051 uncertain significance Ehlers-Danlos syndrome, type 4 2017-08-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 158 of the COL3A1 protein (p.Tyr158Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs756125442, ExAC 0.02%). This variant has not been reported in the literature in individuals with COL3A1-related disease. 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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