ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1165A>T (p.Asn389Tyr) (rs200394946)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181079 SCV000233355 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. Frank et al. (2015) reported the N389Y variant in a 44 year old female with internal carotid dissection and skin hyperelasticity, whose mother and sister harbored the same variant. The mother also had carotid dissection, although skin hyperelasticity segregated independently of the variant in this family (Frank et al., 2015). It has also been seen in multiple individuals referred for Marfan/TAAD testing at GeneDx. Additionally, the N389Y variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.This substitution occurs at a position that is not conserved across species. Nevertheless, the N389Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, while the N389Y variant is within the triple helical region of the COL3A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Ambry Genetics RCV000254267 SCV000320669 uncertain significance Cardiovascular phenotype 2015-12-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000465133 SCV000541785 uncertain significance Ehlers-Danlos syndrome, type 4 2018-04-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 389 of the COL3A1 protein (p.Asn389Tyr). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs200394946, ExAC 0.01%). This variant has been reported in an individual affected with possible vascular Ehlers-Danlos syndrome (PMID: 25758994). ClinVar contains an entry for this variant (Variation ID: 199718). 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: "Possibly 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.
Fulgent Genetics,Fulgent Genetics RCV000465133 SCV000896914 uncertain significance Ehlers-Danlos syndrome, type 4 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000778019 SCV000914129 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-02-06 criteria provided, single submitter clinical testing

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