ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3584G>A (p.Arg1195His) (rs751600209)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522133 SCV000617878 uncertain significance not provided 2017-08-08 criteria provided, single submitter clinical testing The R1195H variant of uncertain significance in the FBN2 gene has not been published as pathogenic or been reported as benign to our knowledge. R1195H is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1195H 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 that is conserved in mammals, however, H1195 is the wild-type residue in at least one species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, although located within a calcium-binding EGF-like domain of the FBN2 gene, the R1195H variant does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with congenital contractural arachnodactyly (Frédéric et al., 2009).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768220 SCV000898704 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2018-11-02 criteria provided, single submitter clinical testing FBN2 NM_001999.3 exon 27 p.Arg1195His (c.3584G>A): This variant has not been reported in the literature and is present in 0.02% (5/24962) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-127673703-C-T). This variant is present in ClinVar (Variation ID:449577). This variant amino acid Histidine (His) is present in multiple species including the naked mole rat, opossum, and mallard duck, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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