ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.8282C>T (p.Ala2761Val) (rs201962592)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000755536 SCV000250254 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The A2761V variant has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for connective tissue disorder genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The A2761V variant was observed in 42/126,410 (0.03%) alleles in individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The A2761V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, the A2761V variant 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 congenital arachnodactyly. (Collod-Beroud et al., 2003; Frédéric et al., 2009). Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000347766 SCV000452539 likely benign Congenital contractural arachnodactyly 2018-01-13 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000347766 SCV000553168 likely benign Congenital contractural arachnodactyly 2020-10-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755536 SCV000603689 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing The p.Ala2761Val variant (rs201962592) has not been reported in the medical literature, gene specific variation databases, but it has been reported to ClinVar (see link below). This variant is listed in the Exome Aggregation Consortium Browser with a population frequency of 0.03 percent (identified on 20 out of 66,740 chromosomes) in non-Finnish European population. The alanine at position 2761 is highly conserved (up to Chicken, considering 11 species) (Alamut v.2.8.1) but Zebra-finch has valine at this position, and this non-cysteine residue is not located in the EGF-like domain. Computational analyses of the effects of the p.Ala2761Val variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Our laboratory has previously identified this variant in one individual with bifid uvula, submucous cleft, micrognathia, facial asymmetry, joint hypermobility, tracheomalacia, conductive hearing loss and developmental delay. Altogether, there is not enough evidence to classify the p.Ala2761Val variant with certainty.
Ambry Genetics RCV000621714 SCV000738992 uncertain significance Cardiovascular phenotype 2020-02-11 criteria provided, single submitter clinical testing The p.A2761V variant (also known as c.8282C>T), located in coding exon 64 of the FBN2 gene, results from a C to T substitution at nucleotide position 8282. The alanine at codon 2761 is replaced by valine, an amino acid with similar properties, and is located in the fibulin-like domain. This amino acid position is not well conserved in available vertebrate species, and valine 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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000347766 SCV000781473 uncertain significance Congenital contractural arachnodactyly 2016-11-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000755536 SCV001501943 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing

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