Submissions for variant NM_000138.5(FBN1):c.4406G>A (p.Arg1469His)

gnomAD frequency: 0.00002  dbSNP: rs397515808

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001182871	SCV001348470	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1469 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 5/282664 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003770013	SCV004575558	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-24	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). 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. This variant disrupts the p.Arg1469 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 29543232), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 922683). This variant is present in population databases (rs397515808, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1469 of the FBN1 protein (p.Arg1469His).
All of Us Research Program, National Institutes of Health	RCV004008334	SCV004814729	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1469 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 been identified in 5/282664 chromosomes 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.