ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5045A>C (p.Tyr1682Ser)

gnomAD frequency: 0.00002  dbSNP: rs769474473
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659623 SCV000781462 likely benign Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV001545405 SCV001764731 uncertain significance not provided 2022-02-02 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009); This variant is associated with the following publications: (PMID: 18767143)
Invitae RCV001868176 SCV002278383 uncertain significance Congenital contractural arachnodactyly 2023-12-03 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 1682 of the FBN2 protein (p.Tyr1682Ser). This variant is present in population databases (rs769474473, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 547360). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN2 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.
Ambry Genetics RCV003163036 SCV003913581 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-03-15 criteria provided, single submitter clinical testing The p.Y1682S variant (also known as c.5045A>C), located in coding exon 39 of the FBN2 gene, results from an A to C substitution at nucleotide position 5045. The tyrosine at codon 1682 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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