ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5788+5G>A (rs193922219)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000035236 SCV000781389 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000035236 SCV000787173 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415118 SCV000492582 pathogenic Ischemic stroke; Arachnodactyly; Aortic root dilatation; Dissecting aortic dilatation; Melanoma; Severe Myopia; Ectopia lentis 2016-05-25 no assertion criteria provided clinical testing
GeneDx RCV000181550 SCV000233853 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The c.5788+5 G>A pathogenic variant in the FBN1 gene (also reported as IVS46+5 G>A due to alternate nomenclature) has been reported in association with clinically diagnosed Marfan syndrome or features of Marfan syndrome and is reported to have occurred de novo in at least five individuals (Nijbroek et al., 1995; Yuan et al., 1999; Loeys et al., 2001; Comeglio et al., 2007; Rommel et al., 2002; Biggin et al., 2004; Arbustini et al., 2005; Sakai et al., 2006; Rand-Hendriksen et al., 2007; Stheneur et al., 2009; Soylen et al., 2009; Baetens et al., 2011, Aalberts et al., 2014). Furthermore, the c.5788+5 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is predicted to destroy the canonical splice donor site in intron 47 and is expected to cause abnormal gene splicing. Additionally, RT-PCR performed on fibroblasts from an individual harboring this variant revealed c.5788+5 G>A leads to in-frame skipping of exon 46 (Nijbroek et al., 1995). Moreover, other splice site variants in the FBN1 gene, including a different nucleotide substitution at the same splice site (c.5788+5 G>T), have been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014).
Integrated Genetics/Laboratory Corporation of America RCV000781375 SCV000919354 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2018-10-08 criteria provided, single submitter clinical testing Variant summary: FBN1 c.5788+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: Four predict the variant abolishes a 5' splicing donor site, while one predicts the variant weakens the same 5' donor site. Two publications report experimental evidence suggesting that this variant causes skipping of exon 46 (Liu_1996; Nijbroek_1995). The variant was absent in 246154 control chromosomes. c.5788+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome, indicating that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000684778 SCV000283640 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-07-02 criteria provided, single submitter clinical testing This sequence change falls in intron 47 of the FBN1 mRNA. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with Marfan syndrome (PMID: 7611299, 14695540, 17657824, 12402346, 11700157, 17663468 ), including several individuals where this variant was detected de novo (PMID: 7611299, 16222657, 19159394). ClinVar contains an entry for this variant (Variation ID: 42394). Experimental studies have shown that this intronic variant results in skipping of exon 47 in a large proportion of protein detected in fibroblasts derived from a mutation carrier (PMID: 7611299). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035236 SCV000058881 pathogenic Marfan syndrome 2014-02-17 criteria provided, single submitter clinical testing The 5788+5G>A variant has been previously reported in >15 individuals with a clinical diagnosis or features of Marfan syndrome, and was reported to have occurred de novo in >10 of these individuals (Nijbroek 1995, Yuan 1999, Loeys 2001, Comeglio 2007, Rommel 2002, Biggin 2004, Arbustini 2005, Sakai 2006, Rand-Hendriksen 2007, Stheneur 2009, Soylen 2009, Baetens 2011, Aalberts 2014, LMM unpublished data). This variant was absent from large population studies. This variant occurs in the highly conserved 5' splicing consensus sequence. Nijbroek et al. (1995) observed skipping of exon 46 in fibroblasts from an affected individual with this variant, which is predicted to result in an abnormal protein product. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
OMIM RCV000035236 SCV000038200 pathogenic Marfan syndrome 2003-09-01 no assertion criteria provided literature only

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