Submissions for variant NM_000138.5(FBN1):c.7383C>G (p.Asn2461Lys)

dbSNP: rs754047254

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586810	SCV000695597	uncertain significance	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7383C>G (p.Asn2461Lys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7383C>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 495645). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793151	SCV000932492	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2461 of the FBN1 protein (p.Asn2461Lys). This variant is present in population databases (rs754047254, gnomAD 0.007%). This missense change has been observed in individual(s) with thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 495645). 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 expected to disrupt FBN1 protein function with a positive predictive value of 95%. 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), which suggests that this may be a clinically significant amino acid residue. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590273	SCV001472854	likely pathogenic	not 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: https://databases.lovd.nl/shared/variants/0000459658#00007761 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.
Ambry Genetics	RCV004619347	SCV005113168	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-28	criteria provided, single submitter	clinical testing	The p.N2461K variant (also known as c.7383C>G), located in coding exon 59 of the FBN1 gene, results from a C to G substitution at nucleotide position 7383. The asparagine at codon 2461 is replaced by lysine, an amino acid with similar properties. This variant alters a conserved residue in the calcium-binding consensus sequence of a cbEGF domain and is expected to disrupt FBN1 function (Handford PA et al. Nature. 1991; 351(6322):164-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000590273	SCV005396421	likely pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20591885)