Submissions for variant NM_000138.5(FBN1):c.287G>C (p.Arg96Thr)

gnomAD frequency: 0.00001  dbSNP: rs794728291

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181644	SCV000233947	likely pathogenic	not provided	2014-07-29	criteria provided, single submitter	clinical testing	p.Arg96Thr (AGG>ACG): c.287 G>C in exon 4 of the FBN1 gene (NM_000138.4)A R96T variant that is likely pathogenic was identified in the FBN1 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R96T 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 R96T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (C89W, C89Y, C100Y, T101A) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in TAAD panel(s).
Ambry Genetics	RCV000243821	SCV000318557	uncertain significance	Cardiovascular phenotype	2019-02-08	criteria provided, single submitter	clinical testing	The p.R96T variant (also known as c.287G>C), located in coding exon 3 of the FBN1 gene, results from a G to C substitution at nucleotide position 287. The arginine at codon 96 is replaced by threonine, an amino acid with similar 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.
Color Diagnostics, LLC DBA Color Health	RCV001190247	SCV001357697	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with threonine at codon 96 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 been reported in two unrelated individuals with clinical features of Marfan syndrome (PMID: 33174221; ClinVar SCV002254511.2). 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.
Invitae	RCV001852286	SCV002254511	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 96 of the FBN1 protein (p.Arg96Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 33174221; Invitae). ClinVar contains an entry for this variant (Variation ID: 200142). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252025	SCV002523351	uncertain significance	See cases	2019-11-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PP2, PP3
Laan Lab, Human Genetics Research Group, University of Tartu	RCV002259318	SCV002538629	likely pathogenic	Marfan syndrome	2021-05-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000181644	SCV003834007	uncertain significance	not provided	2021-03-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537526	SCV004117419	uncertain significance	FBN1-related disorder	2023-09-13	criteria provided, single submitter	clinical testing	The FBN1 c.287G>C variant is predicted to result in the amino acid substitution p.Arg96Thr. This variant was reported in an individual with Marfan syndrome (Hernándiz et al. 2021. PubMed ID: 33174221). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV003991468	SCV004809160	likely pathogenic	Stiff skin syndrome	2024-03-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002259318	SCV004823143	uncertain significance	Marfan syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with threonine at codon 96 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 been reported in two unrelated individuals with clinical features of Marfan syndrome (PMID: 33174221; ClinVar SCV002254511.2). 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.