ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.2648C>A (p.Ser883Tyr) (rs773515722)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199362 SCV000249972 uncertain significance not provided 2018-11-06 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. p.Ser883Tyr (S883Y) TCC>TAC: c.2648 C>A in exon 39 of the COL5A2 gene (NM_000393.3)A variant of unknown significance has been identified in the COL5A2 gene. The S883Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S883Y 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. The S883Y 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 in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with a COL5A2-related disorder, suggesting this region of the protein may be tolerant of change. Also, the S883Y variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of missense mutations occur (Symoens et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD.
Invitae RCV000703509 SCV000832412 uncertain significance Ehlers-Danlos syndrome, classic type 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 883 of the COL5A2 protein (p.Ser883Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213109). 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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