Submissions for variant NM_000138.5(FBN1):c.1837+4C>T

gnomAD frequency: 0.00004  dbSNP: rs199950267

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470131	SCV000544860	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199950267, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 17657824, 31163209). ClinVar contains an entry for this variant (Variation ID: 406295). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001180046	SCV000738377	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-21	criteria provided, single submitter	clinical testing	The c.1837+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 14 in the FBN1 gene. This alteration has been reported in a Marfan syndrome cohort (Madar L et al. J Biotechnol, 2019 Aug;301:105-111). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001180046	SCV001344895	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001662422	SCV001873444	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31163209)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001662422	SCV005877426	likely benign	not provided	2024-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737509	SCV005351153	likely benign	FBN1-related disorder	2024-03-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).