Submissions for variant NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn)

gnomAD frequency: 0.00001  dbSNP: rs794728204

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181486	SCV000233789	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Reported in association with Marfan syndrome or Marfan-like features (Milewicz et al., 1996; Biggin et al., 2004; Stheneur et al., 2009); In vitro functional studies showed that cells with the p.(D1155N) variant had a decreased amount of fibrillin protein deposited into the matrix as compared to control cells (Milewicz et al., 1996); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20564469, 19293843, 17657824, 19002209, 20886638, 14695540, 32679894, 8941093, 20591885)
Invitae	RCV000631998	SCV000753101	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1155 of the FBN1 protein (p.Asp1155Asn). This variant also falls at the last nucleotide of exon 28, which is part of the consensus splice site for this exon. This variant is present in population databases (rs794728204, gnomAD 0.007%). This missense change has been observed in individual(s) with Marfan syndrome and thoracic aortic aneurysm (PMID: 8941093, 14695540, 19002209, 19293843, 20564469, 20886638). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200017). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781378	SCV000919357	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3463G>A (p.Asp1155Asn) results in a conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant also alters a conserved nucleotide located at the end of the exon 28 adjacent to the canonical splice donor site. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251704 control chromosomes. c.3463G>A has been reported in the literature in individuals affected with features of Marfan Syndrome (example, Milewicz_1996, Hilhorst-Hofstee_2010, Biggin_2004, Stheneur_2009, Start_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in decreased incorporation of fibrillin-1 into the pericellular matrix. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000181486	SCV001961508	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002460054	SCV002618034	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-04-03	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.3463G>A (p.D1155N) alteration is located in exon 28 (coding exon 27) of the FBN1 gene. This change occurs in the last base pair of coding exon 27, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration causes the aspartic acid (D) at amino acid position 1155 to be replaced by an asparagine (N). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.3463G>A alteration was observed in 0.0032% (1/31,402) of total alleles studied. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported in multiple individuals in association with Marfan syndrome and related features including ectopia lentis and aortic disease (Milewicz, 1996; Biggin, 2004; Comeglio, 2007; Stheneur, 2009; Aragon-Martin, 2010). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ In one study utilizing in vitro analyses, this alteration did not significantly impact RNA splicing but demonstrated less fibrillin-1 deposition in the extracellular matrix compared with control cells (Milewicz, 1996). The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ BayesDel in silico prediction for the p.D1155N alteration is inconclusive. Based on the BDGP and ESEfinder splice site in silico tools, this alteration is predicted to weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV003147379	SCV003835365	pathogenic	Stiff skin syndrome	2022-07-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002460054	SCV003837673	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-08-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333037	SCV004041194	pathogenic	Marfan syndrome	2023-05-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003333037	SCV004814801	likely pathogenic	Marfan syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1155 in the EGF-like calcium-binding domain of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that cells expressing the mutant protein deposit a decreased amount of fibrillin protein into deposit extracellular matrix compared to control cells (PMID: 8941093). In addition, this variant alters the conserved, last c.G nucleotide of exon 28 and is predicted to affect RNA splicing. RNA studies have produced conflicting results. While one RT-PCR study of patient fibroblasts did not show RNA splicing defect (PMID: 8941093), another study has revealed a 111 bp-insertion in the FBN1 transcript due to the retention of intronic sequence, resulting in the introduction of a premature protein truncation codon (PMID: 9452033). The mutant transcript with the intronic sequence retention represented 22% of total FBN1 mRNA. This variant has been reported in four individuals affected with Marfan syndrome (PMID: 9452033, 14695540, 19293843, 32679894), one individual affected individual with thoracic aortic aneurysm (PMID: 8941093) and two individuals affected with ectopia lentis (PMID: 17657824, 20564469). This variant has been identified in 1/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.