ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.1633C>T (p.Arg545Trp) (rs145258293)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198486 SCV000249960 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. Although the R545W variant has not been published as pathogenic or been reported as benign to our knowledge, it has been identified independently and in conjunction with additional cardiogenetic variants in individuals referred for HDCT genetic testing at GeneDx. However, thus far, segregation data is limited for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. The R545W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the R545W 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). Additionally, the R545W variant is observed 46/276,944 global alleles (0.02%) in large population cohorts (Lek et al., 2016).
Invitae RCV000475939 SCV000547878 uncertain significance Ehlers-Danlos syndrome, classic type 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 545 of the COL5A2 protein (p.Arg545Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs145258293, ExAC 0.03%) but has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213099). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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