ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.2099C>T (p.Thr700Ile) (rs773667668)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200116 SCV000250166 uncertain significance not provided 2017-09-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The T700I variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in one other individual referred for Marfan/TAAD genetic testing at GeneDx, although no clinical details or segregation data are available. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T700I 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, 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, T700I does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene. 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). Furthermore, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity.
Illumina Clinical Services Laboratory,Illumina RCV001151277 SCV001312393 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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