ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.1561A>G (p.Met521Val) (rs535161301)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198488 SCV000249791 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing The M521V variant of uncertain significance in the COL5A1 gene has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The M521V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the 1000 Genomes Project. Although the M521V variant is conserved across species, it is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, the M521V variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of pathogenic missense variants occur (Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000458134 SCV000549009 uncertain significance Ehlers-Danlos syndrome, classic type 2019-07-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 521 of the COL5A1 protein (p.Met521Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs535161301, 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: 212935). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618313 SCV000738653 uncertain significance Cardiovascular phenotype 2018-10-10 criteria provided, single submitter clinical testing Insufficient evidence

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