Submissions for variant NM_000138.5(FBN1):c.7412C>T (p.Pro2471Leu)

dbSNP: rs193922233

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810020	SCV000950206	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2471 of the FBN1 protein (p.Pro2471Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 27906200; Invitae). ClinVar contains an entry for this variant (Variation ID: 654126). 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 expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro2471 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 26017485, 28941062; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001190078	SCV001357492	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2471 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004001719	SCV004816768	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2471 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.