Submissions for variant NM_000138.5(FBN1):c.6872-14A>G

dbSNP: rs1064793119

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001509486	SCV000564995	likely pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 29510914, 35058154, 25907466)
Invitae	RCV000632008	SCV000753111	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 56 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 25907466, 29510914; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 418201). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509486	SCV001716224	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000663907	SCV002025421	uncertain significance	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PP3, PP1, PP4
Molecular Genetics, Royal Melbourne Hospital	RCV000663907	SCV002498630	likely pathogenic	Marfan syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in FBN1 is an intronic variant located in intron 56. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with a clinical diagnosis of Marfan syndrome and a proband with thoracic aortic aneurysm and aortic dissection (PMID: 25907466, 29510914; Royal Melbourne Hospital). It has also been identified as a de novo occurrence with unconfirmed parental relationships in an individual with Marfan syndrome (SCV000787274.1). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by disrupting the acceptor splice site of intron 56 of FBN1 by gain of a de novo acceptor site upstream. This prediction is confirmed by RT-PCR of patient RNA. The assay demonstrated that the variant impacts splicing by use of a cryptic acceptor (unable to determine if complete/partial mis-splicing) within intron 56 (r.6871_6872ins[6872-13_6872-1]) resulting in a frameshift (p.Asp2291Valfs*6; RNA Diagnostics Kid's Neuroscience Centre) leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PS3_Moderate, PS4_Moderate, PM2_Supporting, PM6_Supporting, PP3.
Ambry Genetics	RCV002374878	SCV002667663	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-09-26	criteria provided, single submitter	clinical testing	The c.6872-14A>G intronic pathogenic mutation results from an A to G substitution 14 nucleotides upstream from coding exon 56 in the FBN1 gene. This alteration has been detected in multiple patients with Marfan syndrome (MFS) or MFS-related phenotypes and was reported to be de novo in one individual, although paternity was not confirmed (Proost D et al. Hum. Mutat., 2015 Aug;36:808-14; Hicks KL et al. J. Vasc. Surg., 2018 09;68:701-711; Muiño-Mosquera L et al. Circ Genom Precis Med, 2018 Jun;11:e002039). In addition, this alteration co-segregated with disease in one family tested in our laboratory (Ambry internal data, GeneDx pers. comm.). RNA studies have demonstrated that this mutation creates a new splice acceptor site that is utilized in all transcripts derived from the G allele, resulting in the inclusion of 13 intronic nucleotides and a frameshift (U. Schwarze and P. Byers, Collagen Diagnostic Laboratory, University of Washington, pers. comm.). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Medical Genetics Ghent, University of Ghent	RCV000663907	SCV000787274	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing