ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4801G>A (p.Val1601Ile) (rs762108847)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199119 SCV000250217 uncertain significance not provided 2013-10-21 criteria provided, single submitter clinical testing p.Val1601Ile (GTC>ATC): c.4801 G>A in exon 37 of the FBN2 gene (NM_001999.3) The Val1601Ile variant in the FBN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val1601Ile results in a conservative amino acid substitution of one non-polar amino acid for another at a position that is class conserved across species (however, Ile1601 is present in opossum). In silico analysis predicts Val1601Ile is benign to the protein structure/function. No mutations in nearby residues have been reported in association with contractural arachnodactyly, indicating this region of the protein may be tolerant of change. However, the Val1601Ile variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Val1601Ile is a disease-causing mutation or a rare benign variant. This variant was found in TAAD
Ambry Genetics RCV000248047 SCV000317350 uncertain significance Cardiovascular phenotype 2014-11-20 criteria provided, single submitter clinical testing There is insufficient or conflicting evidence for classification of this alteration.
Illumina Clinical Services Laboratory,Illumina RCV000302604 SCV000452587 likely benign 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 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 RCV000302604 SCV001490250 uncertain significance Congenital contractural arachnodactyly 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1601 of the FBN2 protein (p.Val1601Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs762108847, ExAC 0.01%). This variant has not been reported in the literature in individuals with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213334). 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. 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.

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