Submissions for variant NM_000138.5(FBN1):c.8051+5G>A

gnomAD frequency: 0.00001  dbSNP: rs767384075

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000557828	SCV000628005	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 64 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs767384075, gnomAD 0.005%). This variant has been observed in individual(s) with a FBN1-related disease (PMID: 12938084, 17657824). ClinVar contains an entry for this variant (Variation ID: 457268). 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.
Color Diagnostics, LLC DBA Color Health	RCV001176127	SCV001339994	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-26	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 64 of the FBN1 gene. Splice site prediction tools predict that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who displayed heterogeneous Marfan syndrome-related clinical signs but did not fulfill the criteria for a Marfan syndrome diagnosis (PMID: 17657824). This variant has been identified in 7/280674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre of Medical Genetics, University of Antwerp	RCV002245998	SCV002025472	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PS4, PS1, PP4
Ambry Genetics	RCV001176127	SCV002678430	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-11	criteria provided, single submitter	clinical testing	The c.8051+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 63 in the FBN1 gene. This alteration has been reported in an individual with concerns for Marfan syndrome; however, a clinical diagnosis was not met (Comeglio P et al. Hum Mutat, 2007 Sep;28:928). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV002245998	SCV004824332	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 64 of the FBN1 gene. Splice site prediction tools predict that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who displayed heterogeneous Marfan syndrome-related clinical signs but did not fulfill the criteria for a Marfan syndrome diagnosis (PMID: 17657824). This variant has been identified in 7/280674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525961	SCV005040400	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8051+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 249280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8051+5G>A has been reported in the literature in individuals affected with Aortopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 457268). Based on the evidence outlined above, the variant was classified as uncertain significance.