Submissions for variant NM_000138.5(FBN1):c.4786C>T (p.Arg1596Ter)

dbSNP: rs113871094

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029744	SCV000052397	pathogenic	Marfan syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000029744	SCV000058856	pathogenic	Marfan syndrome	2012-05-02	criteria provided, single submitter	clinical testing	The Arg1596X variant has been reported in 4 individuals with clinical features o f Marfan syndrome and was shown to segregate with clinical feature in one report ed family (Loeys 2001, De Backer 2007, Magyar 2009,). In addition, this variant has been identified in one individual with clinical features of Marfan syndrome by our laboratory. This nonsense variant leads to a premature termination codon at position 1596, which is predicted to lead to a truncated or absent protein. H eterozygous loss of function of the FBN1 gene is an established disease mechanis m in Marfan syndrome. In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM).
GeneDx	RCV000181534	SCV000233837	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); Identified in multiple unrelated individuals with a reported diagnosis of Marfan syndrome, or clinical manifestations of Marfan syndrome, referred for testing at GeneDx and in the published literature (Loeys et al., 2001; Maygar et al., 2009; Stheneur et al., 2009; Ogawa et al., 2011; Han et al., 2017; Zastrow et al., 2017 ); This variant is associated with the following publications: (PMID: 25525159, 21907952, 12938084, 19293843, 19618372, 28901506, 11700157, 17718856, 16756980, 15241795, 11933199, 35058154, 33282382, 31167969, 33461977, 36588568, 29768367, 28050602)
Baylor Genetics	RCV000029744	SCV000328213	pathogenic	Marfan syndrome	2016-01-16	criteria provided, single submitter	clinical testing	This variant has been previously reported (PMID: 11700157) and was seen once in our laboratory de novo in a 3-year-old female with dysmorphisms, developmental delay, autism, hypotonia, relative macrocephaly, failure to thrive, congenital diaphragmatic hernia, recurrent umbilical hernia, pectus carinatum, joint laxity. She also carried a de novo nonsense variant in TRPS1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524501	SCV000544821	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1596*) 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: 11700157, 12938084, 17718856, 19618372, 21907952, 28050602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36082). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515166	SCV000611192	pathogenic	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	2017-05-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170767	SCV001333373	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-02-22	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000181534	SCV001433235	pathogenic	not provided	2020-01-13	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000181534	SCV001446602	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000029744	SCV002025330	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
Ambry Genetics	RCV001170767	SCV003911067	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-12-23	criteria provided, single submitter	clinical testing	The p.R1596* pathogenic mutation (also known as c.4786C>T), located in coding exon 38 of the FBN1 gene, results from a C to T substitution at nucleotide position 4786. This changes the amino acid from an arginine to a stop codon within coding exon 38. This variant has been detected in multiple individuals reported to have Marfan syndrome (MFS) or features consistent with MFS, and individuals from MFS cohorts (Loeys B et al. Arch Intern Med, 2001 Nov;161:2447-54; Spits C et al. Fertil Steril, 2006 Aug;86:310-20; De Backer J et al. Clin Genet, 2007 Sep;72:188-98; Magyar I et al. Hum Mutat, 2009 Sep;30:1355-64; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8Ogawa N et al. Am J Cardiol, 2011 Dec;108:1801-7; Han Q et al. Mol Med Rep, 2017 Nov;16:6620-6625; Hansen J et al. JCI Insight, 2019 Jun 4; Erhart P et al. J Thorac Dis, 2020 Nov;12:6806-6812). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000181534	SCV005414269	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	PP1_strong, PP2, PM2, PS2_moderate, PS4_moderate, PVS1
Center for Medical Genetics Ghent, University of Ghent	RCV000029744	SCV000787089	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000181534	SCV001977778	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000181534	SCV001978373	pathogenic	not provided		no assertion criteria provided	clinical testing