ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4261A>C (p.Ile1421Leu)

dbSNP: rs863223607
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198674 SCV000250294 uncertain significance not provided 2019-07-02 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; 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 (Frederic et al., 2009)
Invitae RCV003765247 SCV004677878 uncertain significance Congenital contractural arachnodactyly 2023-06-03 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 213410). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1421 of the FBN2 protein (p.Ile1421Leu).

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