Submissions for variant NM_000138.5(FBN1):c.1010dup (p.Tyr337Ter)

dbSNP: rs1566918075

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693553	SCV000821426	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2018-04-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr337*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database affected with Marfan syndrome (PMID: 10612827). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic. A different variant (c.1011C>A) giving rise to the same protein effect observed here (p.Tyr337*) has also been reported in an individual affected with Marfan syndrome (PMID: 19863550).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781352	SCV000919326	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-10-06	criteria provided, single submitter	clinical testing	Variant summary: The c.1010dupA (p.Tyr337*) variant in FBN1 gene is a frameshift change that leads to a premature termination at codon 337. This change is predicted to cause loss of normal protein function through protein truncation (loss of the ~7606 amino acids of fibrillin-1 protein (~89%)) or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (121304 and 246054 chrs tested, respectively). The c.1010dupA has been reported in at least one affected individual presented with Classical MFS (UMD data). In addition, another alteration, c.1011C>A, leading to the same amino acid change, p.Tyr377*, has been reported in association with MFS based on the published reports and is cited as Pathogenic by reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197262	SCV001367899	pathogenic	Progeroid and marfanoid aspect-lipodystrophy syndrome	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3.