ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2153C>T (p.Thr718Met)

gnomAD frequency: 0.00001  dbSNP: rs777526851
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181454 SCV000233756 uncertain significance not provided 2022-10-13 criteria provided, single submitter clinical testing 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; Has not been previously published as pathogenic or benign to our knowledge; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 12938084)
Labcorp Genetics (formerly Invitae), Labcorp RCV001043103 SCV001206818 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-02-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 718 of the FBN1 protein (p.Thr718Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs777526851, ExAC 0.001%). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199990). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Color Diagnostics, LLC DBA Color Health RCV001184790 SCV001350859 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-10-14 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 718 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/282900 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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