Submissions for variant NM_000138.5(FBN1):c.8525_8529del (p.Leu2842fs)

dbSNP: rs1064794130

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485375	SCV000567922	pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 30 amino acids are replaced with 6 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 16220557, 19618372, 19839986, 10756346, 32679894, 33910934, 27611364, 24161884, 31098894, 12938084)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659590	SCV000781429	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001063776	SCV001228637	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-05-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Gln2867*) have been determined to be pathogenic (PMID: 19293843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 419823). This premature translational stop signal has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 10756346, 19618372, 27611364). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu2842Profs*7) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the FBN1 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264508	SCV001442698	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8525_8529delTTAAC (p.Leu2842ProfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant was absent in 251280 control chromosomes (gnomAD and publication data). c.8525_8529delTTAAC has been reported in the literature in individuals affected with Marfan Syndrome (Paiz_2000, Hung_2009, Magyar_2009, Aalberts_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and uncertain significance (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002446924	SCV002679158	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-04-04	criteria provided, single submitter	clinical testing	The c.8525_8529delTTAAC pathogenic mutation, located in coding exon 65 of the FBN1 gene, results from a deletion of 5 nucleotides at nucleotide positions 8525 to 8529, causing a translational frameshift with a predicted alternate stop codon (p.L2842Pfs*7). This mutation has been reported in multiple individuals with Marfan syndrome (Palz M et al. Am. J. Med. Genet., 2000 Mar;91:212-21; Rommel K et al. Hum. Mutat., 2005 Dec;26:529-39; Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67; Magyar I et al. Hum. Mutat., 2009 Sep;30:1355-64). 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000659590	SCV000787422	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing