ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.488A>G (p.His163Arg) (rs1029299660)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434872 SCV000529698 uncertain significance not provided 2016-07-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The H163R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H163R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved through mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the H163R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, while the H163R variant is located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a Cysteine residue within this domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with CCA (Collod-Beroud et al., 2003; Frédéric et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000621536 SCV000739003 uncertain significance Cardiovascular phenotype 2017-02-13 criteria provided, single submitter clinical testing The p.H163R variant (also known as c.488A>G), located in coding exon 4 of the FBN2 gene, results from an A to G substitution at nucleotide position 488, and is located in an EGF-like domain. The histidine at codon 163 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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