Submissions for variant NM_001999.4(FBN2):c.6148A>G (p.Lys2050Glu)

gnomAD frequency: 0.00001  dbSNP: rs863223611

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197388	SCV000250302	uncertain significance	not provided	2018-11-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FBN2 gene. The K2050E variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The K2050E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In addition, although the K2050E variant is located within a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with CCA (Collod-Beroud et al., 2003; Frederic et al., 2009).
Invitae	RCV000542082	SCV000630245	uncertain significance	Congenital contractural arachnodactyly	2022-10-25	criteria provided, single submitter	clinical testing	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. 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 FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 213418). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2050 of the FBN2 protein (p.Lys2050Glu).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000542082	SCV002768321	uncertain significance	Congenital contractural arachnodactyly	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant negative is a likely mechanism of disease (PMID: 31316167). (I) 0107 - This gene is associated with autosomal dominant disease. There are also rare reports of a severe form of congenital contractural arachnodactyly due to biallelic variants (PMID: 33571691). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and interfamilial variability is well reported for this gene (PMID: 20301560). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated calcium-binding EGF domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS twice in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003895257	SCV004713903	uncertain significance	FBN2-related condition	2023-12-26	criteria provided, single submitter	clinical testing	The FBN2 c.6148A>G variant is predicted to result in the amino acid substitution p.Lys2050Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.