ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3394G>A (p.Val1132Ile) (rs138834515)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000513490 SCV000250104 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The V1132I variant has not been previously published in association with congenital contractural arachnodactyly (CCA) or other FBN2-related disorder to our knowledge. However, it has been observed in 4/8632 (0.05%) alleles from individuals of East Asian ancestry and in 12/66656 (0.02%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1132I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, while this substitution occurs at a position that is largely conserved across species, isoleucine (I) is the wild-type residue at this position in at least one non-mammalian species. Furthermore, although in silico analysis predicts this variant is probably damaging to the protein structure/function, V1132I does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009). Finally, this variant is also classified as a variant of uncertain significance in ClinVar by other clinical laboratories (ClinVar SCV000317899.1, SCV000553172.1; Landrum et al., 2016).
Ambry Genetics RCV000245259 SCV000317899 uncertain significance Cardiovascular phenotype 2019-12-03 criteria provided, single submitter clinical testing The p.V1132I variant (also known as c.3394G>A), located in coding exon 26 of the FBN2 gene, results from a G to A substitution at nucleotide position 3394. The valine at codon 1132 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species; however, isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000310235 SCV000452610 uncertain significance Congenital contractural arachnodactyly 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000310235 SCV000553172 uncertain significance Congenital contractural arachnodactyly 2020-09-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1132 of the FBN2 protein (p.Val1132Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs138834515, ExAC 0.05%) but has not been reported in the literature in individuals with a FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213228). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000196361 SCV000603678 uncertain significance not specified 2018-07-12 criteria provided, single submitter clinical testing The p.Val1132Ile variant (rs138834515) has not been reported in the medical literature, gene specific variation databases, but has been reported to ClinVar with the classification of uncertain significance. This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.02 percent (identified on 3 out of 13006 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.017 percent (identified on 20 out of 121212 chromosomes). The valine at position 1132 is highly conserved (up to Chicken, considering 11 species) (Alamut v.2.8.1) and is located in an EGF-like calcium domain. However, the p.Val1132Ile variant does not alter a cysteine residue in the EGF-like calcium domain. Cysteines residues in the EGF-like calcium domain are involved in disulfide bonds that are important to the structure of the FBN2 protein and are variants of cysteine amino acids represent the most common class of missense variants reported in congenital contractual arachnodactyly (Frederic 2009). Computational analyses of the effects of the p.Val1132Ile variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Val1132Ile variant with certainty. Pathogenic variant of FBN2 are associated with autosomal dominant congenital contractural arachnodactyly (MIM: 121050) and early-onset macular degeneration (MIM: 616118).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513490 SCV000609175 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659611 SCV000781450 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768222 SCV000898707 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2018-11-02 criteria provided, single submitter clinical testing FBN2 NM_001999.3 exon 26 p.Val1132Ile (c.3394G>A): This variant has not been reported in the literature and is present in 0.03% (7/19946) of East Asian alleles in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:213228). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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