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	uncertain significance	not provided	2024-06-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084, 35535697, 33174221, 37995928)
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852286	SCV002254511	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-03-16	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	2024-06-11	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.