Submissions for variant NM_000138.5(FBN1):c.4459G>A (p.Asp1487Asn)

dbSNP: rs113693945

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663728	SCV003762205	pathogenic	Marfan syndrome	2022-12-01	reviewed by expert panel	curation	The NM_000138 c.4459G>A, is a missense variant in FBN1 predicted to cause a substitution of an Aspartic acid by Asparagine at amino acid 1487 p.(Asp1487Asn). This variant was found in four probands meeting the Ghent criteria (PP4, PS4_strong). The variant segregates with the disease in six affected family members of one proband and three affected family members of another proband (PP1_strong). This variant has been reported three times in ClinVar as likely pathogenic (Variation ID: 549232). It has been reported one time in the literature in a proband with classical Marfan syndrome (PMID: 19293843). This variant is not present in gnomAD v2.1.1 (PM2_sup; https://gnomad.broadinstitute.org/). This variant lies in a critical calcium binding site within a calcium binding EGF domain (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_strong, PM1, PP2, PP3, PP4, PM2_supporting
Invitae	RCV001069593	SCV001234771	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1487 of the FBN1 protein (p.Asp1487Asn). This variant also falls at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843; Invitae). ClinVar contains an entry for this variant (Variation ID: 549232). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 may disrupt the consensus splice site. 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.
Centre of Medical Genetics, University of Antwerp	RCV000663728	SCV002025317	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4
Ambry Genetics	RCV002331297	SCV002635984	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-02	criteria provided, single submitter	clinical testing	The p.D1487N variant (also known as c.4459G>A), located in coding exon 35 of the FBN1 gene, results from a G to A substitution at nucleotide position 4459. The aspartic acid at codon 1487 is replaced by asparagine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 35, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in an individual with classical Marfan syndrome; however, clinical details were not provided (Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526735	SCV005040351	uncertain significance	not specified	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4459G>A (p.Asp1487Asn) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251236 control chromosomes. c.4459G>A has been reported in the literature in individuals affected with Marfan Syndrome. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 549232). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663728	SCV000787064	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing