Submissions for variant NM_000138.5(FBN1):c.7660C>T (p.Arg2554Trp)

gnomAD frequency: 0.00009  dbSNP: rs369294972

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181611	SCV000233914	uncertain significance	not provided	2022-07-25	criteria provided, single submitter	clinical testing	Identified in a patient with incomplete Marfan syndrome and in two relatives with cervical artery dissections in published literature (Comeglio et al., 2007; Grond-Ginsbach et al., 2017); 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 (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 24941995, 25812041, 25637381, 25525159, 24833718, 27647783, 31008308, 31903434, 17657824)
CeGaT Center for Human Genetics Tuebingen	RCV000181611	SCV001149441	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189181	SCV001356416	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2554 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two related individuals affected with cervical artery dissection (PMID: 31008308, 31903434) and in three related individuals affected with atypical Marfan syndrome with major involvement of the cardiovascular system (PMID: 17657824). This variant has been reported in an individual affected with atrioventricular septal heart defect (PMID: 27058611). This variant has also been identified in 9/281700 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.
Invitae	RCV001315977	SCV001506574	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2554 of the FBN1 protein (p.Arg2554Trp). This variant is present in population databases (rs369294972, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17657824, 24833718, 31008308, 31903434; Invitae). ClinVar contains an entry for this variant (Variation ID: 161241). 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.
Ambry Genetics	RCV001189181	SCV002669432	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-10-25	criteria provided, single submitter	clinical testing	The p.R2554W variant (also known as c.7660C>T), located in coding exon 61 of the FBN1 gene, results from a C to T substitution at nucleotide position 7660. The arginine at codon 2554 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in an individual with incomplete Marfan syndrome, in two relatives who suffered internal carotid artery dissection, and in one individual with an atrioventricular septal defect; however, clinical details were limited (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Priest JR et al. PLoS Genet., 2016 Apr;12:e1005963; Grond-Gisbach C et al. Eur Stroke J. 2017:2(2):137-143). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res. 2015;25:305-15). 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.
Fulgent Genetics, Fulgent Genetics	RCV002492541	SCV002791311	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	2021-09-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998169	SCV004816749	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2554 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two related individuals affected with cervical artery dissection (PMID: 31008308, 31903434) and in three related individuals affected with atypical Marfan syndrome with major involvement of the cardiovascular system (PMID: 17657824). This variant has been reported in an individual affected with atrioventricular septal heart defect (PMID: 27058611). This variant has also been identified in 9/281700 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.
CSER _CC_NCGL, University of Washington	RCV000148496	SCV000190204	uncertain significance	Marfan syndrome, incomplete	2014-06-01	no assertion criteria provided	research