ClinVar Miner

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

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Total submissions: 4
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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 RCV001085682 SCV000283460 likely benign Ehlers-Danlos syndrome, type 4 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001085682 SCV001301954 uncertain significance Ehlers-Danlos syndrome, type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV001187409 SCV001354211 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-04-26 criteria provided, single submitter clinical testing

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