ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3296G>A (p.Arg1099His) (rs202050092)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198639 SCV000250188 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing The R1099H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1099H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The R1099H 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; Frederic et al., 2009). While this substitution occurs at a position that is conserved by class, the R1099H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000242556 SCV000317881 uncertain significance Cardiovascular phenotype 2016-06-14 criteria provided, single submitter clinical testing The p.R1099H variant (also known as c.3296G>A), located in coding exon 25 of the FBN2 gene, results from a G to A substitution at nucleotide position 3296. The arginine at codon 1099 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs202050092. Based on data fromExAC, the A allele has an overall frequency less than0.01% (9/106175).Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.51% (1/196) Tuscan alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied and 0.01% (1/8600) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000364863 SCV000452611 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 RCV000364863 SCV000630217 likely benign Congenital contractural arachnodactyly 2020-08-20 criteria provided, single submitter clinical testing

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