ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.2750C>T (p.Pro917Leu) (rs375600865)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195939 SCV000249807 uncertain significance not provided 2014-06-12 criteria provided, single submitter clinical testing p.Pro917Leu (CCG>CTG): c.2750 C>T in exon 34 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 P917L variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The P917L variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P917L 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 across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, there are no missense mutations in nearby residues reported in association with Ehlers-Danlos syndrome.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.This variant was found in TAAD
Invitae RCV000540368 SCV000631476 uncertain significance Ehlers-Danlos syndrome, classic type 2019-01-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 917 of the COL5A1 protein (p.Pro917Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs375600865, ExAC 0.006%) but has not been reported in the literature in individuals with a COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212951). 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. 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 RCV000618043 SCV000738656 uncertain significance Cardiovascular phenotype 2017-01-04 criteria provided, single submitter clinical testing Insufficient evidence

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