Submissions for variant NM_000138.5(FBN1):c.1546C>T (p.Arg516Ter)

dbSNP: rs113812345

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035118	SCV000058758	pathogenic	Marfan syndrome	2020-08-18	criteria provided, single submitter	clinical testing	The p.Arg516X variant in FBN1 has been reported in 5 individuals with Marfan Syndrome and segregated with disease in 1 affected individual (Arbustini 2005 PMID: 16222657, Magyar 2009 PMID: 19618372, Baetens 2011 PMID: 21542060, Aalberts 2014 PMID: 24161884, Yang 2016 PMID: 27234404, Li 2019 PMID: 31098894). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 42285). This nonsense variant leads to a premature termination codon at position 516, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism in Marfan Syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan Syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4.
GeneDx	RCV000181420	SCV000233722	pathogenic	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate no mutant transcript was detected in cycloheximide untreated fibroblasts (Magyar et al., 2009); This variant is associated with the following publications: (PMID: 25525159, 27234404, 19618372, 31098894, 32679894, 34498425, 21542060, 24161884, 25907466, 19293843, 35058154, 16222657, 33174221)
Ambry Genetics	RCV002310640	SCV000319780	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-08-03	criteria provided, single submitter	clinical testing	The p.R516* pathogenic mutation (also known as c.1546C>T) located in coding exon 12 of the FBN1 gene, results from a C to T substitution at nucleotide position 1546. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in several individuals with a clinical diagnosis of Marfan syndrome (Arbustini et al. Hum Mutat. 2005 Nov; 26(5): 494; Baetens et al. Hum Mutat. 2011; 32(9):1053-62; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Stark VC et al. Genes (Basel), 2020 07;11:[Epub ahead of print]). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524496	SCV000544933	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg516*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 16222657, 17657824, 19293843, 19618372, 27234404). ClinVar contains an entry for this variant (Variation ID: 42285). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506581	SCV000603630	pathogenic	not specified	2016-10-31	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000035118	SCV000930530	pathogenic	Marfan syndrome	2016-07-12	criteria provided, single submitter	clinical testing	The p.Arg516* variant present in various studies and been reported in ClinVar by other submitters (ClinVar Variation ID:42285). Evaluation in our clinical center was made with in silico method with the use of NetGene2, Provean, SIFT, MutationTaster. All calculations suggest deleterious/damaging effect. Additionally FBN1 know to be intolerant to LoF variants (deletions, frameshifts, stop-gain, etc.) with ExAC pLI=1.00.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000035118	SCV001934233	pathogenic	Marfan syndrome	2020-10-13	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000035118	SCV002025500	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4 or PM2, PVS1, PP1, PP4
Center for Medical Genetics Ghent, University of Ghent	RCV000035118	SCV000786762	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing