ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.1888C>T (p.Arg630Trp) (rs577618553)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198923 SCV000249800 uncertain significance not provided 2016-06-03 criteria provided, single submitter clinical testing Although the R630W variant has not been published as a pathogenic variant or as a benign variant to our knowledge. The R630W 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. 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, while the R630W variant occurs in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, it does not affect a Glycine residue, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). No missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Finally, the 1000 Genomes Project reports R630W was observed in approximately 0.1% of alleles from individuals of African background. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000559592 SCV000631460 uncertain significance Ehlers-Danlos syndrome, classic type 2019-05-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 630 of the COL5A1 protein (p.Arg630Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs577618553, ExAC 0.01%) but has not been reported in the literature in individuals with a COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212944). 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.
Fulgent Genetics,Fulgent Genetics RCV000559592 SCV000897497 uncertain significance Ehlers-Danlos syndrome, classic type 2018-10-31 criteria provided, single submitter clinical testing

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