Submissions for variant NM_000138.5(FBN1):c.1837+5G>A

dbSNP: rs1445085747

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631930	SCV000753033	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 527158). This variant has been observed in individuals with Marfan syndrome (PMID: 10612827, 14695540, 19839986, 28642162). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change falls in intron 15 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site.
GeneDx	RCV001536170	SCV001752890	likely pathogenic	not provided	2024-07-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis predicts this variant may weaken or destroy the splice donor site in intron 15 and may cause abnormal gene splicing; however, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined; This variant is associated with the following publications: (PMID: 9399842, 14695540, 19839986, 28642162, 10612827, 35058154)
Centre of Medical Genetics, University of Antwerp	RCV000663500	SCV002025515	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Ambry Genetics	RCV002413803	SCV002715038	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-01-14	criteria provided, single submitter	clinical testing	The c.1837+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 14 in the FBN1 gene. This nucleotide position is well conserved in available vertebrate species. This alteration has been detected in one individual with a clinical diagnosis of Marfan syndrome as well as in two individuals with ectopia lentis, one of whom also had skeletal manifestations (Biggin A et al. Hum. Mutat., 2004 Jan;23:99; Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67; Overwater E et al. Eur J Med Genet, 2017 Sep;60:465-473). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002507064	SCV002805506	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	2021-07-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117440	SCV003800652	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1837+5G>A alters a 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: One predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251316 control chromosomes. c.1837+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (Franken_2016, Franken_2017) and other related phenotypes: Dural Ectasia (Hung_2009) and Ectopia Lentis (Biggin_2004, Overwater_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely Pathogenic (n=4) and Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV002413803	SCV004357457	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-02-01	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 15 of the FBN1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in two individuals affected with Marfan syndrome and in an individual suspected of having Marfan syndrome (PMID: 9399842, 19839986, 25652356). This variant has also been reported in another two individuals affected with ectopia lentis (PMID: 14695540, 28642162). This variant has been identified in 1/251316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000663500	SCV004821092	likely pathogenic	Marfan syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 15 of the FBN1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in two individuals affected with Marfan syndrome and in an individual suspected of having Marfan syndrome (PMID: 9399842, 19839986, 25652356). This variant has also been reported in another two individuals affected with ectopia lentis (PMID: 14695540, 28642162). This variant has been identified in 1/251316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663500	SCV000786799	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing