Submissions for variant NM_000138.5(FBN1):c.3012C>G (p.Tyr1004Ter)

dbSNP: rs397515784

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035159	SCV000058800	likely pathogenic	Marfan syndrome	2008-03-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000035159	SCV000678237	pathogenic	Marfan syndrome	2017-08-01	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon25 p.Tyr1004* (c.3012C>G): This variant has not been previously reported in the literature, but has been identified by our laboratory as de novo in 1 individual with a clinical suspicion of Marfan syndrome. This variant is not present in large control databases. This variant is present in ClinVar (Variant ID:42324). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay. Loss of function variants are a known mechanism of disease for this gene (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on the predicted impact to the protein.
GeneDx	RCV000627218	SCV000748206	pathogenic	not provided	2020-09-24	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: 29543232, 24793577)
Invitae	RCV001852707	SCV002236739	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-06-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 24793577, 29543232). ClinVar contains an entry for this variant (Variation ID: 42324). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr1004*) 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).
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000610725	SCV000731217	pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research
Center for Medical Genetics Ghent, University of Ghent	RCV000035159	SCV000786911	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing