ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.6551A>T (p.Asn2184Ile) (rs149071226)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193392 SCV000247367 uncertain significance not specified 2015-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000193392 SCV000250304 uncertain significance not specified 2016-12-19 criteria provided, single submitter clinical testing The N2184I variant of uncertain significance in the FBN2 gene has not been published as a pathogenic or benign variant to our knowledge. The N2184I 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 also occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, although N2184I is located within a calcium-binding EGF-like domain of the FBN2 gene, it does not affect or introduce a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Collod-Beroud et al., 2003; Frédéric et al., 2009). Furthermore, the NHLBI Exome Sequencing Project and the Exome Aggregation Consortium report N2184I was observed in 0.43% to 0.46% of alleles from individuals of African or African American background, indicating it may be a rare benign variant in this population. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
PreventionGenetics,PreventionGenetics RCV000193392 SCV000308634 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000395130 SCV000452566 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000395130 SCV000563033 benign Congenital contractural arachnodactyly 2020-10-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619756 SCV000738948 likely benign Cardiovascular phenotype 2016-02-26 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence

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