Submissions for variant NM_000138.5(FBN1):c.5368C>T (p.Arg1790Ter)

dbSNP: rs113249837

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035224	SCV000058869	pathogenic	Marfan syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.Arg1790X variant in FBN1 has been reported in 6 individuals with clinically diagnosed Marfan Syndrome (fulfilled Ghent criteria) and 3 individuals with clinical features of Marfan-like phenotypes (Marfan syndrome suspected, but not fulfilling Ghent criteria; Arbustini 2005 PMID: 16222657, Sakai 2006 PMID: 16835936, Chung 2009 PMID: 19533785, Magyar 2009 PMID: 19618372, Yoo 2010 PMID: 19863550, Zhurayev 2016 PMID: 27724990, Stengl 2020 PMID: 33059708, Meester 2022 PMID: 35058154. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42382) and was absent from large population studies (gnomAD, v.3.1.2). This nonsense variant leads to a premature termination codon at position 1790, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism of autosomal dominant Marfan syndrome. In summary, this variant meets criterion to be classified as pathogenic for autosomal dominant Marfan Syndrome. ACMG/AMP Criteria applied: PM2_supporting, PSV1, PS4_Moderate.
GeneDx	RCV000181541	SCV000233844	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	Has been reported several times in association with Marfan syndrome or other Marfan-like syndrome in unrelated patients referred for genetic testing at GeneDx and in the published literature (Arbustini et al., 2005; Sakai et al., 2006; Howarth et al., 2007; Chung et al., 2009; Magyar et al., 2009; Yoo et al., 2010; Stengl et al., 2020); 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; This variant is associated with the following publications: (PMID: 16222657, 19533785, 16835936, 17627385, 19293843, 26787436, 19863550, 19618372, 33059708)
Ambry Genetics	RCV002310642	SCV000319217	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-07-25	criteria provided, single submitter	clinical testing	The p.R1790* pathogenic mutation (also known as c.5368C>T), located in coding exon 43 of the FBN1 gene, results from a C to T substitution at nucleotide position 5368. This alteration changes the amino acid from an arginine to a stop codon within coding exon 43. This mutation has been reported in numerous Marfan syndrome cohorts (e.g., Arbustini E et al. Hum Mutat. 2005;26(5):494; Magyar I et al. Hum. Mutat. 2009;30:1355-64; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Franken R et al. Eur. Heart J, 2016;37:3285-3290). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684816	SCV000544859	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1790*) 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 premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 16222657, 16835936, 19533785, 19618372, 19863550, 26787436). ClinVar contains an entry for this variant (Variation ID: 42382). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000035224	SCV000781385	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000035224	SCV001976805	pathogenic	Marfan syndrome	2021-10-05	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Centre of Medical Genetics, University of Antwerp	RCV000035224	SCV002025343	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
All of Us Research Program, National Institutes of Health	RCV000035224	SCV004827283	pathogenic	Marfan syndrome	2023-11-08	criteria provided, single submitter	clinical testing	The c.5368C>T (p.Arg1790*) variant in of the FBN1 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been identified in numerous individuals (>10) affected with clinical features of Marfan syndrome (PMID:16222657, 19618372, 16835936, 19533785, 19863550, 19293843, 17627385, 26787436). Loss of function variants are known to be pathogenic for FBN1 (PMID: 17701892, 30286810, 21063442, 17657824, 19293843). Truncating variants downstream of this variant are reported in individuals with Marfan syndrome (PMID: 27906200, 31730815, 24793577). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 42382). Therefore, the c.5368C>T (p.Arg1790*) variant in the FBN1 gene is classified as pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000035224	SCV000787127	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing