Submissions for variant NM_000138.5(FBN1):c.7412C>G (p.Pro2471Arg)

gnomAD frequency: 0.00006  dbSNP: rs193922233

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181602	SCV000052431	uncertain significance	not specified	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7412C>G (p.Pro2471Arg) results in a non-conservative amino acid change located in an EGF-like repeat domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 1,614,000 control chromosomes (gnomAD v4.1 dataset). This frequency is not higher than the estimated maximum expected for a pathogenic variant in FBN1 causing Marfan Syndrome (0.00011), allowing no conclusion about variant significance. c.7412C>G has been reported in the literature in individuals affected with suspected Marfan Syndrome (MS) and MS-related conditions including abdominal aortic aneurysm, thoracic aortic disease, mitral prolapse and ectopia lentis (e.g. Baudhuin_2015, van de Luijtgaarden_2015, Campens_2015, Vatti_2017, Gago-Diaz_2017, Clark_2019). However, in some of these cases co-occurring variants could potentially explain the phenotype (Vatti_2017, van Wjingaarden_2020), although an additive effect of these variants cannot be excluded. These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25652356, 25644172, 31019026, 28391405, 28941062, 32277046, 26017485). ClinVar contains an entry for this variant (Variation ID: 36115). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000766959	SCV000233905	uncertain significance	not provided	2024-04-21	criteria provided, single submitter	clinical testing	Segregated with disease in some affected relatives, but the variant was absent in other affected relatives (PMID: 25652356); Reported in a female with mitral valve prolapse and premature ventricular contractions who also harbors a pathogenic variant in the DSP gene (PMID: 32277046); Although located in a calcium-binding EGF-like domain of the FBN1gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28391405, 31019026, 26017485, 28941062, 25644172, PuppoMoreno2023, 25652356, 32277046, 12938084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474840	SCV000544932	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2471 of the FBN1 protein (p.Pro2471Arg). This variant is present in population databases (rs193922233, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 25644172, 25652356, 26017485, 28941062; Invitae). ClinVar contains an entry for this variant (Variation ID: 36115). 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 determined to be pathogenic (PMID: 27906200). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504828	SCV002814927	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-11-02	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000029777	SCV000787329	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000766959	SCV001797976	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766959	SCV001970117	uncertain significance	not provided		no assertion criteria provided	clinical testing