Submissions for variant NM_000138.5(FBN1):c.6163+2dup

gnomAD frequency: 0.00001  dbSNP: rs794728315

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV002470796	SCV004704627	uncertain significance	Marfan syndrome	2024-02-22	reviewed by expert panel	curation	The NM_00138 c.6163+2dup variant in FBN1 occurs in the intron near the invariant region (+1/2) of the consensus donor splice site; the c.6163+2T nucleotide is moderately conserved. In silico prediction programs (GeneSplicer, MaxEntScan, NNSplice) predict this variant to weaken/ destroy the canonical donor site of this intron, which is expected to disrupt mRNA splicing and result in absent or truncated protein product (PP3). However, this prediction has not been confirmed by RNA functional studies. This variant has been reported five times in ClinVar: once as pathogenic, four times as uncertain significance (Variation ID: 200167). This variant has been reported in individuals with thoracic aortic aneurysm and/or dissection who carried other cardiogenetic variants (GeneDx, Murdoch Childrens Research Institute ClinVar entry). It has also been reported in an individual without structural heart disease (PMID 28659821). This variant is present in 2/113448 (0.0018%) of alleles tested from the European non-Finnish population in gnomAD (https://gnomad.broadinstitute.org/ v2.1.1). Due to the conflicting evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP3.
GeneDx	RCV000181670	SCV000233973	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2014-07-18	criteria provided, single submitter	clinical testing	c.6163+2dupT: IVS50+2_50+3insT in intron 50 of the FBN1 gene (NM_000138.4)Although the c.6163+2_6163+3insT c.6163+2dupT mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, in silico splice prediction algorithms predict that this mutation destroys the canonical splice donor site in intron 50, causing abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.6163+2dupT in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317131	SCV000695577	uncertain significance	not specified	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6163+2dupT 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 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 8e-06 in 251092 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6163+2dupT in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28659821). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000181670	SCV001348904	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-25	criteria provided, single submitter	clinical testing	This variant alters the splice donor site in intron 50 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 an individual affected with bicuspid aortic valve-associated thoracic aortic aneurysm (PMID: 28659821). This variant has been identified in 2/251092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001239673	SCV001412564	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 50 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. This variant is present in population databases (rs794728315, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200167). 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 disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470796	SCV002768079	uncertain significance	Marfan syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is associated with autosomal dominant disease however, autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). The canonical splice site is not predicted to be affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools. (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The variant c.6163+3A>G, which also introduces a change to nucleotide +3, has been reported in an individual with Marfan syndrome (PMID: 12203992). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once as pathogenic in ClinVar and was seen in two individuals who each harboured additional cardiogenetic variants. One of these individuals presented with a thoracic aortic aneurysm in adulthood, and the second individual presented with a ventricular septal defect and aortic dilation (GeneDx personal communication). This variant also has multiple VUS entries in ClinVar, including one report of an individual with no personal history of a cardiovascular disorder or a Marfan syndrome diagnosis (Color Health personal communication). Furthermore, in a large bicuspid aortic valve/thoracic aortic aneurysm cohort study, this variant was identified in a control individual with no structural heart disease (PMID: 28659821). (I) 0903 - This variant has limited evidence for segregation with disease. The variants segregates with disease in three affected individuals in this family. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign