ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3565C>T (p.His1189Tyr)

gnomAD frequency: 0.00001  dbSNP: rs779690646
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199489 SCV000250283 uncertain significance not provided 2019-12-04 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Collod-Beroud et al., 2003; Frederic et al., 2009)
Invitae RCV000542698 SCV000630222 uncertain significance Congenital contractural arachnodactyly 2023-10-20 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1189 of the FBN2 protein (p.His1189Tyr). This variant is present in population databases (rs779690646, 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: 213399). 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 not expected to disrupt 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.

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