ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2084C>A (p.Pro695His)

dbSNP: rs1555399754
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521308 SCV000619738 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing The P695H variant in the FBN1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P695H 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. In addition, 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. We interpret P695H as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003766957 SCV004569859 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-09-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 451090). This missense change has been observed in individual(s) with clinical features of FBN1-related condtions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 695 of the FBN1 protein (p.Pro695His). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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