Submissions for variant NM_000138.5(FBN1):c.8326C>T (p.Arg2776Ter)

gnomAD frequency: 0.00001  dbSNP: rs137854466

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000017901	SCV005387632	pathogenic	Marfan syndrome	2024-08-22	reviewed by expert panel	curation	The NM_00138 c.8326C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 96 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). In an in-vitro microfibril assay, this variant was reported to result in intracellular retention of the protein (PMID 24982166; PS3). This variant was found in a proband with aortic aneurysm and dissection, ectopia lentis, and skeletal features, who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported 10 times in ClinVar, nine as pathogenic and once as likely pathogenic (Variation ID: 16439). Several other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (internal lab data, PMID 9338581, 31098894, 31730815, 33059708, 25907466, 19293843, 34916231; PS4). In one individual with aortic dissection and myopia, this variant was reported to be de novo without confirmation of parental relationships (PMID 31098894; 0.25 points). In two families with MFS, this variant was found to segregate with disease in five affected family members (internal lab data; PP1_Strong). This variant is present in in 10/24982 (0.04%) of alleles tested from the Finnish population in gnomAD and did not pass the quality control criteria in the genome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PS4, PS3, PP1_Strong, PM2_Sup, PP4
GeneDx	RCV000181630	SCV000233933	pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	Functional studies suggest that the variant results in intra-cellular retention of the protein (Jensen et al., 2014); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 96 amino acid residues are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (HGMD; Lonnqvist et al., 1998; Ritty et al., 1999; Jensen et al., 2014); This variant is associated with the following publications: (PMID: 9817919, 10085138, 11826022, 24982166, 7911051, 10756346, 19293843, 33059708, 33824467, 31098894, 9338581, 31730815, 34008892)
Ambry Genetics	RCV002310993	SCV000320556	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-01-03	criteria provided, single submitter	clinical testing	The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at nucleotide position 8326. This changes the amino acid from an arginine to a stop codon within coding exon 65. This alteration occurs at the 3' terminus of theFBN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 96 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, which is also known as p.R1878*, c.5632C>T, has been reported in multiple individuals with Marfan syndrome (Hayward C et al. Hum. Mutat., 1994;3:159-62; Körkkö J et al. J. Med. Genet., 2002 Jan;39:34-41; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Jensen SA et al. Proc Natl Acad Sci U S A, 2014 Jul;111:10155-60; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Stengl R et al. Orphanet J Rare Dis, 2020 10;15:290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000181630	SCV000340055	pathogenic	not provided	2016-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631918	SCV000753021	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-10-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Leu2854Profs*9, p.Gln2830*, p.Leu2854Profs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 16439). This premature translational stop signal has been observed in individual(s) with FBN-1 related conditions (PMID: 7911051, 9338581, 11826022). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2776*) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the FBN1 protein.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000017901	SCV000930047	pathogenic	Marfan syndrome	2019-07-19	criteria provided, single submitter	clinical testing	At our clinical center The p.R2776* variant was found in one family and one unrelated individual. This variant present in variouas individual studies reported by other submitters (ClinVar entry - Variation ID:16439), as well as present in population studies (C=0.00001 (1/121406, ExAC)). Functional study of the variant (PMID: 24982166) shows its pathogenic mechanism by linkage of the immature monomers, thus it behaves as a dominant-negative mutation, disrupting not only the mutant protein, but the normal one, which is synthesized from the unchanged allele.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374806	SCV001439507	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000017901	SCV001976751	pathogenic	Marfan syndrome	2021-08-10	criteria provided, single submitter	clinical testing	PVS1, PP3, PP5
Centre of Medical Genetics, University of Antwerp	RCV000017901	SCV002025475	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PS4, PS1, PP4 or PS4, PS1, PP1, PP4
OMIM	RCV000017901	SCV000038180	pathogenic	Marfan syndrome	1994-01-01	no assertion criteria provided	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000017901	SCV000052447	pathogenic	Marfan syndrome	2015-04-09	no assertion criteria provided	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000017901	SCV000787408	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing