ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.2536G>A (p.Glu846Lys) (rs375666281)

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 RCV000196819 SCV000250276 uncertain significance not specified 2016-10-11 criteria provided, single submitter clinical testing The E846K variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E846K 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 where amino acids with similar properties to Glutamate are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with CCA, suggesting this region of the protein may be tolerant of change. Finally, although the E846K variant is located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a Cysteine residue within this domain. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with CCA (Collod-Beroud et al., 2003). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000405761 SCV000452626 likely benign Congenital contractural arachnodactyly 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000405761 SCV000553213 uncertain significance Congenital contractural arachnodactyly 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 846 of the FBN2 protein (p.Glu846Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs375666281, ExAC 0.03%), 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 a FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213392). 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 C0"). In summary, this variant has uncertain impact on FBN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619797 SCV000738421 uncertain significance Cardiovascular phenotype 2018-07-14 criteria provided, single submitter clinical testing The p.E846K variant (also known as c.2536G>A), located in coding exon 19 of the FBN2 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a patient with suspicion of Marfan syndrome, but this variant was not thought to be responsible for the clinical phenotype (Caylor RC et al. Neurogenetics, 2018 Aug;19(3):205-213). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001281014 SCV001468418 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2020-08-10 criteria provided, single submitter clinical testing FBN2 NM_001999.3 exon 19 p.Glu846Lys (c.2536G>A): This variant has not been reported in the literature but is present in 0.02% (37/129150) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-127697434-C-T). This variant is present in ClinVar (Variation ID:213392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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.