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

gnomAD frequency: 0.00006  dbSNP: rs375487064

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766976	SCV000250288	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this variant does not alter splicing
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	2023-12-12	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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs375487064, gnomAD 0.01%). This variant has been observed in individuals with clinical features of congenital contractural arachnodactyly and/or thoracic aortic aneurysm and/or dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 213404). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Illumina Laboratory Services, 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.
Ambry Genetics	RCV002354548	SCV002649006	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-06-16	criteria provided, single submitter	clinical testing	The c.5800+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 45 in the FBN2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002500604	SCV002778233	uncertain significance	Congenital contractural arachnodactyly; Macular degeneration, early-onset	2022-03-07	criteria provided, single submitter	clinical testing