ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.2490G>A (p.Pro830=) (rs777361888)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222293 SCV000279654 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. The silent c.2490 G>A variant has not been published as pathogenic or been reported as benign to our knowledge. The c.2490 G>A 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). While this variant results in a synonymous amino acid change at residue P830, at least two in silico splice prediction programs predict this variant may result in aberrant gene splicing by creating a cryptic splice donor site upstream of the natural donor site in intron 36. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Furthermore, this substitution occurs at a nucleotide that is not conserved across species and Adenine is the wild-type nucleotide at this position in at least three species. Lastly, the c.2490 G>A 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). Substitution of the triplet glycine residue is a well-established pathogenic mechanism for vascular EDS (Pepin et al., 2015). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000232339 SCV000283460 likely benign Ehlers-Danlos syndrome, type 4 2017-11-27 criteria provided, single submitter clinical testing

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