Submissions for variant NM_000138.5(FBN1):c.4460-8G>A

gnomAD frequency: 0.00001  dbSNP: rs193922204

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029737	SCV000052390	likely pathogenic	Marfan syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Blueprint Genetics	RCV000029737	SCV000263915	pathogenic	Marfan syndrome	2015-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000429823	SCV000515903	likely pathogenic	not provided	2021-11-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); This single nucleotide substitution occurs upstream of the natural splice acceptor site in intron 36 and creates a new cryptic splice acceptor site. Two publications independently reported that cDNA sequence analysis demonstrated the result of this variant to be in-frame insertion of 6 nucleotides into the coding sequence (c.4459_4460insTTTTAG) (Loeys et al., 2001; Pepe et al., 2007).; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19293843, 18087243, 32679894, 11700157)
Invitae	RCV000524498	SCV000544952	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 36 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is present in population databases (rs193922204, gnomAD 0.003%). This variant has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 19293843; Invitae). This variant is also known as IVS35-8G>A. ClinVar contains an entry for this variant (Variation ID: 36075). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507229	SCV000603671	likely pathogenic	not specified	2017-04-03	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768217	SCV000898693	likely pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-11-11	criteria provided, single submitter	clinical testing	FBN1 NM_000138 exon 37 c.4460-8G>A: This variant has been reported in the literature in at least 3 individuals with features or a clinical suspicion of Marfan syndrome, segregating with disease in 2 affected family members (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243, Stheneur 2009 PMID:19293843). This variant is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs193922204). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:36075). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Additional studies suggest that this variant may activate a cryptic acceptor site and impact the protein (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243). However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Ambry Genetics	RCV002326689	SCV002635546	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-11-10	criteria provided, single submitter	clinical testing	The c.4460-8G>A intronic variant results from a G to A substitution 8 nucleotides upstream from coding exon 36 in the FBN1 gene. This variant was reported in individuals with features of Marfan syndrome (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Loeys B et al. Hum. Mutat., 2004 Aug;24:140-6; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). In one family, this variant segregated with ectopia lentis in 3 relatives and RT-PCR analysis demonstrated an inframe insertion of 6 nucleotides due to use of a cryptic acceptor site (Pepe G et al. Mol. Vis., 2007 Nov;13:2242-7). Using four different splice site prediction tools, this alteration is predicted by ESEFinder, MaxEnt, and HSF to create a new alternate splice acceptor site, but BDGP does not predict the creation of a non-native acceptor site, nor a deleterious effect on splicing; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Based on data from gnomAD, the A allele has an overall frequency of approximately <0.001% (1/250992). This nucleotide position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000029737	SCV002766718	likely pathogenic	Marfan syndrome	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been confirmed by reverse transcriptase PCR (RT-PCR) to activate a cryptic acceptor splice site resulting in an insertion of six intronic nucleotides in exon 36 (c.4459_4460insTTTTAG). The variant results in an in-frame insertion of two amino acids in the protein sequence, p.(Thr1486_Asp1487insValLeu) (PMID: 18087243). (N) 0213 - In-frame insertion in a non-repetitive region that has high conservation. (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. In-frame insertion not compatible. (N) 0600 - Variant is located in an annotated domain or motif. The insertion occurs between calcium-binding, EGF-like domain 25 and 26, which are normally adjacent to each other (PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. In-frame insertion variants in this region have been reported as likely pathogenic and as VUS in ClinVar. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Five likely pathogenic and two pathogenic entries in ClinVar. Previously reported in multiple patients with Marfan syndrome and ectopia lentis (PMID: 18087243, PMID: 11700157, PMID: 19293843) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000029737	SCV004847813	likely pathogenic	Marfan syndrome	2019-08-07	criteria provided, single submitter	clinical testing	The c.4460-8G>A variant in FBN1 has been reported in at least 3 individuals with Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Loeys 2001, Pepe 2007, Stheneur 2009). It has also been identified in 0.003% (1/34574) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 36075). This variant is located in the 3' splice region. Computational tools and in vitro splicing assays (Pepe 2007) predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting, PS4_Moderate.
Center for Medical Genetics Ghent, University of Ghent	RCV000029737	SCV000787066	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing