ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3385G>A (p.Asp1129Asn) (rs199802059)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000659485 SCV000781300 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000198241 SCV000249980 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. The D1129N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 9/65508 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The D1129N 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 predicts this variant is probably damaging to the protein structure/function. However, the D1129N 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 pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Invitae RCV000688546 SCV000816163 uncertain significance Ehlers-Danlos syndrome, classic type 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1129 of the COL5A2 protein (p.Asp1129Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs199802059, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213117). 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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