Submissions for variant NM_000138.5(FBN1):c.247+1G>A

dbSNP: rs25404

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035141	SCV000058782	pathogenic	Marfan syndrome	2012-03-20	criteria provided, single submitter	clinical testing	The 247+1G>A variant (FBN1) has been reported in 8 individuals with clinical fea tures of Marfan syndrome and showed segregation with clinical features in two fa mily members (Dietz 1993, Halliday 1999, Chikumi 2000, Guo 2001, Schrijver 2002, Turner 2008). This variant was also reported to have occurred de novo in one in dividual (Guo 2001). The 247+1G>A variant occurs in the invariant region (+/- 1 /2) of the splice consensus sequence and functional analyses reveal that this ch ange results in the skipping of exon 2 and the creation of a frameshift. This f rameshift is predicted to alter the protein?s amino acid sequence beginning at p osition 55 and lead to a premature termination codon 45 amino acids downstream ( Dietz 1993, Guo 2001). Heterozygous loss of function of the FBN1 gene is an est ablished disease mechanism in Marfan syndrome. In summary, this variant meets ou r criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
GeneDx	RCV000181642	SCV000233945	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant causes skipping of exon 2, which creates a frameshift and introduces a premature termination codon (Dietz et al., 1993; Guo et al., 2001); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34498425, 25525159, 12161601, 11391655, 27647783, 28855619, 22772377, 23506379, 12068374, 31098894, 31825148, 32679894, 8406497, 35058154)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526514	SCV000627858	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Marfan syndrome (PMID: 8406497, 10647894, 10721679, 11391655, 12068374, 17657824, 19161152, 22772377). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42307). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770680	SCV000902143	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-02-26	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000035141	SCV002025560	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
Ambry Genetics	RCV000770680	SCV002738274	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-11-17	criteria provided, single submitter	clinical testing	The c.247+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the FBN1 gene. This alteration has been reported in individuals with Marfan syndrome, and was found to cause out-of-frame exon skipping that leads to reduced RNA expression (Dietz HC et al. Genomics, 1993 Aug;17:468-75). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000035141	SCV000038196	pathogenic	Marfan syndrome	2000-01-01	no assertion criteria provided	literature only