ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4407G>A (p.Pro1469=) (rs546172367)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250514 SCV000319277 likely benign Cardiovascular phenotype 2014-06-24 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000807074 SCV000947106 uncertain significance Congenital contractural arachnodactyly 2018-10-10 criteria provided, single submitter clinical testing This sequence change affects codon 1469 of the FBN2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN2 protein. This variant is present in population databases (rs546172367, ExAC 0.002%). This variant has not been reported in the literature in individuals with FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 263838). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285896 SCV001472400 uncertain significance none provided 2020-02-07 criteria provided, single submitter clinical testing The FBN2 c.4407G>A; p.Pro1469Pro variant (rs546172367), to our knowledge, is not reported in the medical literature but is reported with conflicting interpretations of pathogenicity in ClinVar (Variation ID: 263838). This variant is found on only three chromosomes (3/251314 alleles) in the Genome Aggregation Database. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic splice site, although RNA analyses would be required to confirm this. Given the lack of clinical and functional data, the significance of the c.4407G>A variant is uncertain at this time.

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