ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7193C>T (p.Thr2398Ile)

dbSNP: rs1169351376
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001182631 SCV001348144 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-03-06 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 2398 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 FBN1-related disorders in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003770004 SCV004595347 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-11-03 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2398 of the FBN1 protein (p.Thr2398Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 922516). 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 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.
All of Us Research Program, National Institutes of Health RCV004008314 SCV004822397 uncertain significance Marfan syndrome 2023-10-23 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 2398 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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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