Submissions for variant NM_000138.5(FBN1):c.5875A>G (p.Asn1959Asp)

gnomAD frequency: 0.00001  dbSNP: rs956702513

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179432	SCV001344093	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 1959 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001307462	SCV001496875	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-04	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 1959 of the FBN1 protein (p.Asn1959Asp). This variant is not present in population databases (gnomAD no frequency). 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: 920583). 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 not expected to disrupt FBN1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Phosphorus, Inc.	RCV001823759	SCV002073471	uncertain significance	not specified	2022-01-19	criteria provided, single submitter	clinical testing	This missense variant results in a substitution of asparagine with aspartic acid at codon 1959 of the FBN1 gene (transcript NM_000138.4). This variant has been reported in ClinVar (920583) NM_000138.5 (FBN1):c.5875A>G (p.Asn1959Asp). The variant has not occurred in population databases. This position is conserved. In silico functional algorithms agree, predicting it as benign (PolyPhen/REVEL) and tolerated (SIFT), but no functional studies were performed to confirm these predictions. The variant has not occurred in the literature associated with the disease. In conclusion, the available evidence is insufficient to determine the pathogenicity of this variant. Therefore, it is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002497627	SCV002776544	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	2021-11-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004006562	SCV004814623	uncertain significance	Marfan syndrome	2023-10-27	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 33 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant 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 is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.