Submissions for variant NM_000138.5(FBN1):c.1468+5G>A

dbSNP: rs397515757

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035117	SCV000058757	pathogenic	Marfan syndrome	2017-02-23	criteria provided, single submitter	clinical testing	The c.1468+5G>A variant in FBN1 has been reported in 9 individuals with clinical features of Marfan syndrome (Aalberts 2014, Baetens 2011, Comeglio 2007, Liu 19 97-1998, LMM data). It has not been identified in large population studies. In a ddition, this variant has segregated with disease in 5 affected individuals from one family tested by our laboratory. The c.1468+5G>A variant is located in the 5' splice region and RNA studies have revealed this splice site variant leads to abnormal splicing and exon skipping in FBN1 (Aalberts 2014, Ogawa 2011, Liu 199 7-1998), resulting in an abnormal or absent protein. Heterozygous loss of functi on of the FBN1 gene is an established disease mechanism in Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosoma l dominant Marfan syndrome based on its recurrence in multiple affected individu als, segregation in families, extremely low allele frequency in the general popu lation, and functional impact on splicing.
GeneDx	RCV000181432	SCV000233734	pathogenic	not provided	2022-01-24	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Published functional studies demonstrate that c.1468+5 G>A destroys the natural splice donor site and results in abnormal splicing (Ogawa et al., 2011); This variant is associated with the following publications: (PMID: 29543232, 31730815, 25525159, 17657824, 19949477, 19339519, 25907466, 24161884, 21542060, 17627385, 11702223, 27085269, 11933199, 33726816, 10464652, 25101912, 21907952, 34498425)
Ambry Genetics	RCV000251716	SCV000318198	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-12-07	criteria provided, single submitter	clinical testing	The c.1468+5G>A intronic pathogenic mutation (also known as c.IVS11+5G>A) results from a G to A substitution 5 nucleotides after coding exon 11 in the FBN1 gene. This mutation has been detected in individuals with classical Marfan syndrome and in individuals with Marfan-related features, including isolated ectopia lentis, thoracic aortic aneurysm and dissections, and/or skeletal findings (Liu WO et al. Genet Test. 1997-1998;1:237-42; Comeglio P et al. Hum Mutat. 2007;28:928; Aalberts JJ et al. Gene, 2014 Jan;534:40-3; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). RNA studies found that a cryptic splice donor site within exon 11 can become activated in the presence of this alteration, which leads to loss of a critical region of the protein (Ogawa N et al. Am J Cardiol. 2011;108:1801-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000515263	SCV000611190	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	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000631905	SCV000753008	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 17627385, 17657824, 25101912, 25907466). In at least one individual the variant was observed to be de novo. This variant is also known as IVS11+5G>A. ClinVar contains an entry for this variant (Variation ID: 42284). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in creation of a new donor splice site and introduces a premature termination codon (PMID: 21907952). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000035117	SCV000781331	likely pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000035117	SCV000863468	pathogenic	Marfan syndrome	2018-12-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000251716	SCV000901057	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-04-11	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000035117	SCV002025466	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226174	SCV003922533	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1468+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: Two predict abolishing and two predict severe weakening of the 5' splice site. RNA studies found that a cryptic donor site in exon 11 became activated, resulting in loss of critical region (Ogawa_2011). The variant was absent in 251358 control chromosomes. c.1468+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (Example: Baetens_2011, Liu_1997, Hogwarth_2007, Ogawa_2011, Comeglio_2007 etc.). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=9) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000035117	SCV000206958	pathogenic	Marfan syndrome	2014-05-16	no assertion criteria provided	clinical testing
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000251716	SCV000731214	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research
Center for Medical Genetics Ghent, University of Ghent	RCV000035117	SCV000786754	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing