Submissions for variant NM_000138.5(FBN1):c.1961-1G>A

dbSNP: rs2043686634

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171258	SCV001333966	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251260	SCV001426775	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2020-07-06	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1961-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251370 control chromosomes (gnomAD). c.1961-1G>A has been reported in the literature (Groth_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In the HGMD database, there is another nucleotide change noted in the surrounding position (e.g. c.1961-3T>G,). One ClinVar submitter (evaluation after 2014) cite the variant as as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873580	SCV002310360	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-01-29	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 27906200). ClinVar contains an entry for this variant (Variation ID: 915817). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 16 of the FBN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843).