Submissions for variant NM_000138.5(FBN1):c.8198C>G (p.Thr2733Arg)

gnomAD frequency: 0.00001  dbSNP: rs794728340

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181709	SCV000234012	uncertain significance	not provided	2014-09-05	criteria provided, single submitter	clinical testing	p.Thr2733Arg (ACA>AGA): c.8198 C>G in exon 65 of the FBN1 gene (NM_000138.4) A variant of unknown significance has been identified in the FBN1 gene. The T2733R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The T2733R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T2733R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, only one missense mutations in a nearby residue (R2726W) has been reported in association with Marfan syndrome, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).
Ambry Genetics	RCV001181848	SCV000738931	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-11-29	criteria provided, single submitter	clinical testing	The p.T2733R variant (also known as c.8198C>G), located in coding exon 64 of the FBN1 gene, results from a C to G substitution at nucleotide position 8198. The threonine at codon 2733 is replaced by arginine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042367	SCV001206045	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181848	SCV001347089	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 2733 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 1/31390 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.
All of Us Research Program, National Institutes of Health	RCV003996706	SCV004844914	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces threonine with arginine at codon 2733 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 been identified in 1/30962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.