ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.6253C>G (p.Pro2085Ala) (rs34845843)

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 RCV000196188 SCV000250227 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The P2085A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in other individuals referred for Marfan/TAAD genetic testing at GeneDx, although no segregation data are available to further clarify the role of this variant in disease. Additionally, the P2085A variant has been observed in 19/66688 (0.03%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P2085A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, while P2085A is located within a calcium-binding EGF-like domain of the FBN2 gene, this variant 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 FBN2-related disorders (Frederic et al., 2009). Lastly, although a different missense variant at the same residue (P2085T) has been reported in association with adolescent idiopathic scoliosis (Buchan et al., 2014), the clinical significance of this variant also remains to be definitely determined.
Ambry Genetics RCV000246374 SCV000318111 likely benign Cardiovascular phenotype 2018-12-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV000357755 SCV000452571 likely benign Congenital contractural arachnodactyly 2018-01-13 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 RCV000357755 SCV000754857 benign Congenital contractural arachnodactyly 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000600 SCV001157587 uncertain significance none provided 2020-01-16 criteria provided, single submitter clinical testing The FBN2 c.6253C>G; p.Pro2085Ala variant (rs34845843), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 213344). It is observed in the general population at an overall frequency of 0.024% (68/282576 alleles) with increased frequency in the Ashkenazi Jewish population (0.41%) in the Genome Aggregation Database. The proline at codon 2085 is highly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.

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.