Submissions for variant NM_000138.5(FBN1):c.1844A>G (p.Asn615Ser)

gnomAD frequency: 0.00001  dbSNP: rs397515763

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035127	SCV000058767	uncertain significance	not specified	2011-10-21	criteria provided, single submitter	clinical testing	The Asn615Ser variant has not been previously reported in the literature or been identified by our laboratory. The amino acid asparagine (Asp) at position 615 i s conserved across mammals but not into lower species. In the absence of additi onal information, such as control studies, segregation data, or functional analy ses, the clinical significance of this variant cannot be determined with certain ty at this time. The clinical significance of this variant should be interprete d in the context of this individual's clinical manifestation.
GeneDx	RCV000766933	SCV000233746	uncertain significance	not provided	2014-01-18	criteria provided, single submitter	clinical testing	p.Asn615Ser (AAC>AGC): c.1844 A>G in exon 16 of the FBN1 gene (NM_000138.4)The A615S variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The A615S variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. In silico analysis predicts N615S may be benign to the protein structure/function. However, the Asn615 residue is conserved in mammals. Furthermore, mutations in nearby residues (C611R, D613N, E616K, E616G, C617G) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein. The N615 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if N615S is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659511	SCV000781335	uncertain significance	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001192096	SCV001360069	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 615 of the FBN1 protein. Computational prediction tools indicate that this variant may have an uncertain impact on protein structure and function. 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 4/282838 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.
Ambry Genetics	RCV001192096	SCV002717061	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-06-05	criteria provided, single submitter	clinical testing	The p.N615S variant (also known as c.1844A>G), located in coding exon 15 of the FBN1 gene, results from an A to G substitution at nucleotide position 1844. The asparagine at codon 615 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well 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.
Fulgent Genetics, Fulgent Genetics	RCV002490469	SCV002794021	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	2021-10-07	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000659511	SCV003839077	uncertain significance	Marfan syndrome	2023-01-13	criteria provided, single submitter	clinical testing	This FBN1 missense variant (rs397515763) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282838 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar (Variation ID 42293), but to our knowledge, has not been reported in individuals with FBN1-related disorders in the literature. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated. The asparagine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of c.1844A>G; p.Asn615Ser in FBN1 to be uncertain at this time.
All of Us Research Program, National Institutes of Health	RCV000659511	SCV004823027	uncertain significance	Marfan syndrome	2023-12-18	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 10 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 has been identified in 4/277178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.