ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4642G>A (p.Val1548Ile) (rs140313460)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199274 SCV000250214 uncertain significance not specified 2017-01-05 criteria provided, single submitter clinical testing The V1548I variant of uncertain significance in the FBN2 gene has not been published as a pathogenic variant or beenreported as a benign variant to our knowledge. This variant has been identified in multiple unrelated individualsreferred for Marfan/TAAD genetic testing at GeneDx, although segregation data from these individuals is not sufficientto determine the pathogenicity of this variant. While it was not observed with any significant frequency in individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project andthe Exome Aggregation Consortium report that the V1548I variant was observed in approximately 0.1% of allelesfrom individuals of South Asian background, indicating it may be a rare benign variant in this population. Thissubstitution occurs at a position that is conserved by class; however, I1548 is tolerated in at least one species. TheV1548I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. Consequently, in silico analysis is inconsistent in its predictions as to whetheror not the variant is damaging to the protein structure/function. Finally, the V1548I variant does not affect a Cysteineresidue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-bindingEGF-like domains represent the majority of pathogenic missense changes associated with congenital arachnodactyly(Collod-Beroud et al., 2003; Frédéric et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000620571 SCV000738954 uncertain significance Cardiovascular phenotype 2016-02-25 criteria provided, single submitter clinical testing The p.V1548I variant (also known as c.4642G>A), located in coding exon 36 of the FBN2 gene, results from a G to A substitution at nucleotide position 4642. The valine at codon 1548 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs140313460. Based on data fromExAC, the A allele has an overall frequency of approximately 0.02% (23/121394). The highest observed frequency was 0.06% (11/16510) of South Asian alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: [Accessed February 25, 2016]).Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (3/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles and 0.02% (2/8600) European American alleles. This amino acid position is well conserved in available vertebrate species; however, isoleucineis 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 variant remains unclear.
Invitae RCV000863851 SCV001004573 likely benign Congenital contractural arachnodactyly 2019-07-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000863851 SCV001314068 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.

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