ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.6946A>T (p.Ile2316Phe) (rs201220519)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197843 SCV000250308 uncertain significance not specified 2016-10-03 criteria provided, single submitter clinical testing p.Ile2316Phe (ATC>TTC): c.6946 A>T in exon 55 of the FBN2 gene (NM_001999.3) The I2316F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I2316F variant was not observed with any significant frequency in approximately 6500 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 I2316F 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. 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 TAADV2-1,TAAD
Ambry Genetics RCV000247632 SCV000318326 likely benign Cardiovascular phenotype 2019-05-24 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Invitae RCV000469864 SCV000553195 uncertain significance Congenital contractural arachnodactyly 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 2316 of the FBN2 protein (p.Ile2316Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs201220519, 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 FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213423). 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: Probably Damaging; Align-GVGD: Class C1). 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. 5
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487809 SCV000575435 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000197843 SCV000603699 uncertain significance not specified 2019-04-19 criteria provided, single submitter clinical testing The p.Ile2316Phe variant (rs201220519) has not been reported in the scientific literature but it is listed in the ClinVar database, where it has been classified by a different laboratory as a variant of uncertain significant (see link below). This variant is listed in the Exome Variant Server at an overall allele frequency of 0.015% (identified in 2 out of 13,006 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser at an overall allele frequency of 0.018% (identified in 22 out of 121,306 chromosomes). The isoleucine at codon 2316 is highly conserved considering 11 species (Alamut software v2.7.1), and computational analyses suggest this variant may have a significant impact on FBN2 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing).
Illumina Clinical Services Laboratory,Illumina RCV000469864 SCV001316129 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000487809 SCV001715860 uncertain significance not provided 2019-11-25 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000581293 SCV000692235 uncertain significance Craniosynostosis syndrome 2017-07-28 no assertion criteria provided clinical testing

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