ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5602A>T (p.Ile1868Phe)

gnomAD frequency: 0.00015  dbSNP: rs150931558
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523867 SCV000617170 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The I1868F variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/10402 (0.08%) alleles from individuals of African ancestry in the Exome Aggregation (ExAC) dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the I1868F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to isoleucine are tolerated across species. Finally, while the I1868F variant is located within 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 congenital contractural arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al., 2009).
Labcorp Genetics (formerly Invitae), Labcorp RCV001224815 SCV001397038 benign Congenital contractural arachnodactyly 2024-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV004619311 SCV005113203 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-06-14 criteria provided, single submitter clinical testing The p.I1868F variant (also known as c.5602A>T), located in coding exon 44 of the FBN2 gene, results from an A to T substitution at nucleotide position 5602. The isoleucine at codon 1868 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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