ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4447G>A (p.Gly1483Arg)

dbSNP: rs794728223
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181521 SCV000233824 uncertain significance not provided 2022-10-06 criteria provided, single submitter clinical testing Identified in a cohort of patients with mitral valve prolapse (MVP) in published literature (van Wijangaarden et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Although located in a calcium-binding EGF-like domain of the FBN1 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 FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32277046, 34826401, 12938084)
Institute of Human Genetics, University Hospital Muenster RCV002287381 SCV002577842 likely pathogenic Abnormality of connective tissue 2021-12-20 criteria provided, single submitter clinical testing ACMG categories: PS1,PM2,PP5
Ambry Genetics RCV002326983 SCV002638408 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-08-08 criteria provided, single submitter clinical testing The p.G1483R variant (also known as c.4447G>A), located in coding exon 35 of the FBN1 gene, results from a G to A substitution at nucleotide position 4447. The glycine at codon 1483 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV003996688 SCV004826125 uncertain significance Marfan syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 1483 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.

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