Submissions for variant NM_000138.5(FBN1):c.6354C>T (p.Ile2118=)

gnomAD frequency: 0.00001  dbSNP: rs112989722

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000017912	SCV000058886	pathogenic	Marfan syndrome	2019-04-22	criteria provided, single submitter	clinical testing	The p.Ile2118Ile variant has been identified in 6 individuals with clinical features of Marfan syndrome and segregated in 7 affected relatives (Liu 1997, Miller 2007, Attanasio 2008, Pilop 2009, Pees 2014, Trujillo Quintero 2017). In addition, this variant has been identified as a de novo variant in one affected individual by our laboratory (paternity/maternity not confirmed). This variant has also been identified in 1/19938 East Asian and 1/128572 European chromosomes by gnomAD (gnomAD https://gnomad.broadinstitute.org/). Although this variant does not lead to an amino acid change, functional studies have shown that this variant induces the skipping of exon 51 leading to the in-frame deletion of 22 amino acids (Liu 1997). Therefore, this variant meets criteria to be classified as pathogenic. ACMG/AMP codes applied: PP1_Strong; PM2; PM6; PS3_Moderate; PS4.
Ambry Genetics	RCV002310629	SCV000319336	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2014-11-11	criteria provided, single submitter	clinical testing	The c.6354C>T pathogenic mutation (also known as p.I2118I), located in coding exon 51 of the FBN1 gene, results from a C to T substitution at nucleotide position 6354. This nucleotide substitution does not change the amino acid at codon 2118. However, this alteration results in in-frame skipping of the entire exon 51 based on RT-PCR analysis (Liu W et al. Nat Genet. 1997;16(4):328-9). This recurrent alteration disrupts an exonic splicing enhancer and has been reported in multiple patients (Miller TE et al. Genet Med. 2007;9(1):23-33; Attanasio M et al. Clin Genet. 2008;74(1):39-46; Pilop C et al. Circulation. 2009;120(11):983-91; Pees C et al. Clin Genet. 2013). Based on the supporting evidence, c.6354C>T is interpreted as a disease-causing mutation.
GeneDx	RCV000483725	SCV000564993	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published RT-PCR studies demonstrated that c.6354 C>T results in skipping of exon 52 (reported as exon 51) (PMID: 9241263); This variant is associated with the following publications: (PMID: 18435798, 24199744, 34550612, 37107549, 16995940, 11137998, 33801742, 34281902, 36729443, 17224687, 9241263, 28117189, 19720936)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589136	SCV000695579	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2019-12-16	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6354C>T results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publication reports experimental evidence that this variant affects mRNA splicing (Liu_1997, Kashima_2007, Miller_2007). The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. c.6354C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Liu_1997, Miller_2007, Attanasio_2008, Pilop_2009, Trujillo-Quintero_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704427	SCV000833376	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 52 (also known as exon 51), but is expected to preserve the integrity of the reading-frame (PMID: 9241263, 16995940, 17224687, 17884807). ClinVar contains an entry for this variant (Variation ID: 16449). This variant has been observed in individual(s) with Marfan syndrome (PMID: 9241263, 17224687, 18435798, 19720936, 24199744, 28117189). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs112989722, gnomAD 0.005%). This sequence change affects codon 2118 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000017912	SCV001433473	pathogenic	Marfan syndrome	2019-10-24	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000017912	SCV005415850	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Moderate+PS4+PP1_Strong
OMIM	RCV000017912	SCV000038191	pathogenic	Marfan syndrome	1997-08-01	no assertion criteria provided	literature only