Submissions for variant NM_000138.5(FBN1):c.5603C>G (p.Thr1868Arg)

dbSNP: rs145082616

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176528	SCV001340545	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 1868 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 3/250890 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	RCV001221690	SCV001393750	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with arginine at codon 1868 of the FBN1 protein (p.Thr1868Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. 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: "Benign"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483953	SCV002788784	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-08-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001176528	SCV004057897	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-08	criteria provided, single submitter	clinical testing	The p.T1868R variant (also known as c.5603C>G), located in coding exon 45 of the FBN1 gene, results from a C to G substitution at nucleotide position 5603. The threonine at codon 1868 is replaced by arginine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV004006303	SCV004814644	uncertain significance	Marfan syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 1868 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 3/250890 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.