ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.1805C>T (p.Pro602Leu) (rs749007253)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200619 SCV000249798 uncertain significance not provided 2015-03-02 criteria provided, single submitter clinical testing p.Pro602Leu (P602L) CCG>CTG: c.1805 C>T in exon 16 of the COL5A1 gene (NM_000093.3)Approximately 46% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A1 gene (Malfait F et al., 2011). The P602L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P602L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P602L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with EDS, indicating that this region of the protein may be tolerant of change. Furthermore, P602L 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 missense mutations occur (Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.5 This variant was found in TAADV2-1
Ambry Genetics RCV000621566 SCV000738652 uncertain significance Cardiovascular phenotype 2016-12-22 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000798084 SCV000937680 uncertain significance Ehlers-Danlos syndrome, classic type 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 602 of the COL5A1 protein (p.Pro602Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs749007253, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212942). 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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