Submissions for variant NM_000138.5(FBN1):c.4226_4227del (p.Cys1408_Ser1409insTer)

dbSNP: rs1566905976

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702122	SCV000830958	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2018-04-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1409*) 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 not been reported in the literature in individuals with FBN1-related disease. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193501	SCV001362383	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4226_4227delCT (p.Ser1409X) 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 by our laboratory (eg. c.4621C>T, p.Arg1541X; c.4930C>T, p.Arg1644X). The variant was absent in 251442 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4226_4227delCT in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509494	SCV001716233	pathogenic	not provided	2019-09-23	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4
Ambry Genetics	RCV002332485	SCV002629647	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-08-17	criteria provided, single submitter	clinical testing	The c.4226_4227delCT pathogenic mutation, located in coding exon 34 of the FBN1 gene, results from a deletion of two nucleotides at nucleotide positions 4226 to 4227, causing a translational frameshift with a predicted alternate stop codon (p.S1409*). 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.