ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5855T>C (p.Val1952Ala) (rs372879535)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001085 SCV001158219 uncertain significance not specified 2019-02-28 criteria provided, single submitter clinical testing The FBN2 c.5855T>C; p.Val1952Ala variant (rs372879535), to our knowledge, is not described in the medical literature or in gene-specific databases. It is observed in the general population at a low overall frequency of 0.0028% (8/282804 alleles) in the Genome Aggregation Database. The valine at codon 1952 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027824 SCV001190444 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2019-11-14 criteria provided, single submitter clinical testing FBN2 NM_001999.3 exon 46 p.Val1952Ala (c.5855T>C): This variant has not been reported in the literature but is present in 0.02% (5/24966) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-127638727-A-G). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae RCV001066192 SCV001231194 uncertain significance Congenital contractural arachnodactyly 2019-02-08 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1952 of the FBN2 protein (p.Val1952Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs372879535, ExAC 0.02%). This variant has not been reported in the literature in individuals with FBN2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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