ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5447C>T (p.Pro1816Leu) (rs149537608)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200857 SCV000250298 uncertain significance not provided 2013-02-07 criteria provided, single submitter clinical testing p.Pro1816Leu (CCA>CTA): c.5447 C>T in exon 43 of the FBN2 gene (NM_001999.3) The Pro1816Leu variant in the FBN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro1816Leu results in a semi-conservative amino acid substitution resulting in a loss of a sterically-constrained Proline residue at a position that is conserved across species. The Pro1816Leu variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Nevertheless, no mutations in nearby codons have been reported in association with congenital contractural arachnodactyly. Also, in silico analysis predicts Pro1816Leu is benign to the protein structure/function. This variant was found in TAAD
Illumina Clinical Services Laboratory,Illumina RCV000352887 SCV000452582 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001181 SCV001158333 uncertain significance not specified 2019-04-15 criteria provided, single submitter clinical testing The FBN2 c.5447C>T; p.Pro1816Leu variant (rs149537608), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 213414). It is observed in the general population at an overall frequency of 0.01% (26/251280 alleles) with increased frequency in the Ashkenazi Jewish population (0.21%) in the Genome Aggregation Database. The proline at codon 1816 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.

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