Submissions for variant NM_000138.5(FBN1):c.3145G>A (p.Gly1049Ser)

gnomAD frequency: 0.00004  dbSNP: rs778181932

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555743	SCV000627886	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1049 of the FBN1 protein (p.Gly1049Ser). This variant is present in population databases (rs778181932, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 457190). 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.Gly1049 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV001177886	SCV001342185	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1049 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 5/282892 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197236	SCV001367873	uncertain significance	Progeroid and marfanoid aspect-lipodystrophy syndrome	2019-05-10	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,,PM5,PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323592	SCV004030038	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3145G>A (p.Gly1049Ser) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3145G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004003783	SCV004814829	uncertain significance	Marfan syndrome	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1049 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/282892 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001702671	SCV004847274	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	The p.Gly1049Ser variant in FBN1 has not been previously reported in individuals with Marfan syndrome or familial thoracic aortic aneurysm and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 457190). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One variant involving this codon (p.Gly1049Asp) has been identified in individuals with Marfan syndrome or thoracic aortic aneurysm and dissection. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702671	SCV001927511	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702671	SCV001976226	uncertain significance	not provided		no assertion criteria provided	clinical testing