Submissions for variant NM_000138.5(FBN1):c.50T>C (p.Leu17Ser)

dbSNP: rs794728201

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181478	SCV000233781	uncertain significance	not provided	2014-05-29	criteria provided, single submitter	clinical testing	p.Leu17Ser (TTA>TCA): c.50 T>C in exon 2 of the FBN1 gene (NM_000138.4)A variant of unknown significance has been identified in the FBN1 gene. The L17S variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The L17S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L17S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense mutations in nearby residues (L11R, Y20C) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein. Nevertheless, this substitution occurs at a position that is not conserved across species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001351547	SCV001546027	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 17 of the FBN1 protein (p.Leu17Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200011). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN1 protein function with a negative predictive value of 95%. 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.