ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.8082C>A (p.His2694Gln) (rs142755118)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000659022 SCV000250134 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The H2694Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed, both independently and in conjunction with additional cardiogenetic variants, in multiple unrelated individuals referred for Marfan/TAAD or connective tissue disorder genetic testing at GeneDx. In addition, the H2694Q variant was observed in 92/126522 (0.07%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The H2694Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, although the H2694Q variant occurs 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 congenital arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al., 2009).
Invitae RCV000228951 SCV000287280 likely benign Congenital contractural arachnodactyly 2020-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000245722 SCV000318709 uncertain significance Cardiovascular phenotype 2018-04-17 criteria provided, single submitter clinical testing The p.H2694Q variant (also known as c.8082C>A), located in coding exon 63 of the FBN2 gene, results from a C to A substitution at nucleotide position 8082. The histidine at codon 2694 is replaced by glutamine, an amino acid with highly similar properties, and is located in the COOH unique region domain. <span style="background-color:initial">This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species<span style="background-color:initial">. 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 RCV000228951 SCV000452543 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000659022 SCV000703497 uncertain significance not provided 2016-12-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000659022 SCV000780826 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283625 SCV000883879 uncertain significance none provided 2020-04-07 criteria provided, single submitter clinical testing The FBN2 c.8082C>A; p.His2694Gln variant (rs142755118, ClinVar variant ID 213254), to our knowledge, is not reported in the medical literature or gene specific variation databases, but it has been previously identified by our laboratory in two patients referred for symptoms of aortopathy, as well as one patient’s apparently asymptomatic parent. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.07% (identified on 92 out of 126,522 chromosomes). The histidine at position 2694 is highly conserved, considering 11 species, and computational analyses of the effects of the p.His2694Gln variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.His2694Gln variant cannot be determined with certainty.
GenomeConnect, ClinGen RCV000228951 SCV001423252 not provided Congenital contractural arachnodactyly no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 02-27-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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