Submissions for variant NM_000138.5(FBN1):c.1148-2A>G

dbSNP: rs397515756

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035116	SCV000058756	pathogenic	Marfan syndrome	2020-08-07	criteria provided, single submitter	clinical testing	The c.1148-2A>G variant in FBN1 has been identified in an individual with Marfan syndrome (Comeglio 2007 PubMed: 17657824) and was absent in large population studies. This variant is reported in ClinVar (allele ID: 539856). One additional variants involving this position (c.1148-2A>T) has been reported as a de novo variant in an individual with clinical features of Marfan syndrome (Cao 2018 PubMed: 30101859). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1; PM2; PM5; PS4_Supporting.
GeneDx	RCV000480005	SCV000567946	pathogenic	not provided	2015-09-09	criteria provided, single submitter	clinical testing	The c.1148-2 A>G variant was reported previously in association with Marfan syndrome by Comeglio et al., (2007) and was absent from 160 control chromosomes. The c.1148-2 A>G substitution destroys the canonical splice acceptor site in intron 10 and is predicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Many other splice site variantsin the FBN1 gene have been reported in HGMD in association with Marfan syndrome (Stenson P et al., 2014). Furthermore, the c.1148-2 A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.1148-2 A>G as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780240	SCV000917348	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2018-03-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1148-2A>G 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: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 243460 control chromosomes. c.1148-2A>G has been reported in the literature in individuals affected with Marfan Syndrome. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001852705	SCV002238816	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-09-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 42283). Disruption of this splice site has been observed in individuals with FBN1-related conditions (PMID: 17657824, 31211624). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 10 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). For these reasons, this variant has been classified as Pathogenic.