Submissions for variant NM_000138.5(FBN1):c.3766A>G (p.Asn1256Asp)

dbSNP: rs772890884

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001180697	SCV001345693	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-02-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces asparagine with aspartic acid at codon 1256 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/245904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Molecular Lab, Department of Haematology, Christian Medical College	RCV002249763	SCV002516041	uncertain significance	Geleophysic dysplasia 2	2022-05-20	criteria provided, single submitter	clinical testing
Molecular Lab, Department of Haematology, Christian Medical College	RCV002249762	SCV002516042	uncertain significance	Acromicric dysplasia	2022-05-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001180697	SCV002619737	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-04-14	criteria provided, single submitter	clinical testing	The p.N1256D variant (also known as c.3766A>G), located in coding exon 30 of the FBN1 gene, results from an A to G substitution at nucleotide position 3766. The asparagine at codon 1256 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was reported in an individual with Marfan-like features; however, clinical details were limited (Seo GH et al. Medicine (Baltimore), 2018 May;97:e10767). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769971	SCV004579220	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1256 of the FBN1 protein (p.Asn1256Asp). This variant is present in population databases (rs772890884, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 29768367; internal data). ClinVar contains an entry for this variant (Variation ID: 921344). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn1256His amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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.
All of Us Research Program, National Institutes of Health	RCV004006683	SCV004814779	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces asparagine with aspartic acid at codon 1256 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/245904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.