ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1338T>A (p.Arg446=)

gnomAD frequency: 0.00001  dbSNP: rs1553507953
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521054 SCV000618361 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing The R446R (c.1338 T>A) variant has not been published as pathogenic or been reported as benign to our knowledge. It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R446R (c.1338 T>A) variant occurs at a nucleotide position that is not conserved across species. However, two of three splice algorithms predict the creation of a significantly strong cryptic splice donor site upstream of the canonical splice donor site of exon 19, which may result in aberrant gene splicing. Moreover, other exonic splice site variants in the COL3A1 gene have been reported in HGMD in association with vascular Ehlers-Danlos syndrome (vEDS, EDS type IV) (Stenson et al., 2014). Nonetheless, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Labcorp Genetics (formerly Invitae), Labcorp RCV002525143 SCV003521451 likely benign Ehlers-Danlos syndrome, type 4 2022-10-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003528182 SCV004361466 likely benign Familial thoracic aortic aneurysm and aortic dissection 2023-12-05 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV002525143 SCV004827054 uncertain significance Ehlers-Danlos syndrome, type 4 2023-08-28 criteria provided, single submitter clinical testing This synonymous variant is predicted to activate a cryptic splice donor site within exon 19 of the COL3A1 gene. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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