ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5800+5G>A (rs375487064)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766976 SCV000250288 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing The c.5800+5G>A variant in the FBN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, it has been observed in multiple unrelated individuals tested for aortic aneurysm or dissection at GeneDx. The c.5800+5G>A substitution occurs at a nucleotide position that is conserved across species. This variant reduces the quality of the splice donor site in intron 45, and is expected to cause abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Furthermore, although other splice site variants in the FBN2 gene have been reported in the Human Gene Mutation Database in association with FBN2-related disorders, no splice site variants have been reported downstream of the c.5800+5 G>A variant (Stenson et al., 2014). The c.5800+5G>A variant is observed in 12/111,450 alleles (0.011%) from individuals of non-Finnish European background, and 16/245,894 global alleles (0.0065%), in large population cohorts (Lek et al., 2016). We therefore interpret c.5800+5G>A as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000197552 SCV000603685 uncertain significance not specified 2016-08-25 criteria provided, single submitter clinical testing
Invitae RCV000528713 SCV000630241 uncertain significance Congenital contractural arachnodactyly 2020-10-18 criteria provided, single submitter clinical testing This sequence change falls in intron 45 of the FBN2 gene. It does not directly change the encoded amino acid sequence of the FBN2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs375487064, ExAC 0.009%) but has not been reported in the literature in individuals with a FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213404). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000528713 SCV001315314 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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