ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7383C>G (p.Asn2461Lys) (rs754047254)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590273 SCV000695597 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.7383C>G (p.Asn2461Lys) variant located in the EGF-like #38 domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/121314 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. In addition, the variant does not alter or create a Cysteine, which plays a key role in proper FBN1 protein function. Therefore, because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000793151 SCV000932492 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 2461 of the FBN1 protein (p.Asn2461Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs754047254, ExAC 0.01%). This variant has been observed in an individual with clinical features of thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 495645). 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 C0"). This variant disrupts the p.Asn2461 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 26787436), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286308 SCV001472854 likely pathogenic none provided 2019-12-07 criteria provided, single submitter clinical testing The FBN1 c.7383C>G; p.Asn2461Lys variant (rs754047254), to our knowledge, is not reported in the medical literature but is reported in the LOVD database (see link). This variant is reported in ClinVar (Variation ID: 495645), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 2461 is highly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, this asparagine residue is located in the conserved residues of an EGF consensus sequence, which is a common mechanism of pathogenicity (Wu 1995). Additionally, other variants at this codon (c.7381A>C; p.Asn2461His; c.7382A>C; p.Asn2461Thr) have been reported in individuals with Marfan syndrome (Franken 2016, Stheneur 2009). Based on available information, this variant is considered to be likely pathogenic. References: Link to LOVD: Franken R et al. Genotype impacts survival in Marfan syndrome. Eur Heart J. 2016 Nov 14;37(43):3285-3290. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Wu YS et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem Biol. 1995 2(2):91-7.

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