ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3839C>T (p.Ser1280Leu) (rs200481467)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000513271 SCV000250286 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing The S1280L variant of uncertain significance in the FBN2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been seen in other individuals referred for heritable disorders of connective tissue testing at GeneDx. S1280L has also been observed in 13/126,530 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The S1280L 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. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, although this variant is located within a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with congenital contractural arachnodactyly (Collod-Beroud et al., 2003; Frederic et al., 2009).
Invitae RCV000472155 SCV000553192 uncertain significance Congenital contractural arachnodactyly 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1280 of the FBN2 protein (p.Ser1280Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs200481467, 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 FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213402). 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: "Benign"; Align-GVGD: "Class C25"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513271 SCV000609174 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620430 SCV000739037 uncertain significance Cardiovascular phenotype 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GenomeConnect, ClinGen RCV000513271 SCV000840353 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.