Submissions for variant NM_000138.5(FBN1):c.3373C>T (p.Arg1125Ter)

dbSNP: rs727505006

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156427	SCV000206145	pathogenic	Marfan syndrome	2014-03-06	criteria provided, single submitter	clinical testing	The Arg1125X variant in FBN1 has been reported in six individuals with clinical features of Marfan syndrome (Attanasio 2008, Comeglio 2007, Hung 2009, Rommel 20 05, Stheneur 2009, Sheikhzadeh 2012). This nonsense variant leads to a premature termination codon at position 1125, which is predicted to lead to a truncated o r absent protein. Heterozygous loss of function of the FBN1 gene is an establish ed disease mechanism in Marfan syndrome. In summary, this variant meets our crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM). The presenc e of a heterozygous pathogenic variant in FBN1 is consistent with a diagnosis of Marfan syndrome, but this information should be reconciled with the complete cl inical history of this individual.
Invitae	RCV000557569	SCV000627892	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1125*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 179632). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 16220557, 19839986, 23684891, 27011056, 29357934, 29907982). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV000578572	SCV000680524	pathogenic	not provided	2020-12-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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: 21883168, 24941995, 31730815, 25525159, 16220557, 19012347, 19293843, 19618372, 27011056, 18435798, 19839986, 17657824, 29907982, 29357934, 31536524)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000156427	SCV000740509	pathogenic	Marfan syndrome	2016-11-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770676	SCV000902138	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-03-30	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000156427	SCV002025577	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
Ambry Genetics	RCV000770676	SCV005032470	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-11-15	criteria provided, single submitter	clinical testing	The p.R1125* pathogenic mutation (also known as c.3373C>T), located in coding exon 27 of the FBN1 gene, results from a C to T substitution at nucleotide position 3373. This changes the amino acid from an arginine to a stop codon within coding exon 27. This variant has been detected in multiple unrelated individuals with Marfan syndrome (MFS), or features consistent with a diagnoses of MFS (Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Attanasio M et al. Clin Genet, 2008 Jul;74:39-46; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67; Sheikhzadeh S et al. Clin Genet, 2012 Sep;82:240-7; Becerra-Muñoz VM et al. Orphanet J Rare Dis, 2018 Jan;13:16; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Li Y et al. Am J Transl Res, 2021 May;13:4281-4295; Meester JAN et al. Genet Med, 2022 May;24:1045-1053). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000156427	SCV000786957	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing