rs794728204
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.3463G>A(p.Asp1155Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1155G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3463G>A | p.Asp1155Asn | missense_variant, splice_region_variant | 28/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.3463G>A | p.Asp1155Asn | missense_variant, splice_region_variant | 27/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3463G>A | p.Asp1155Asn | missense_variant, splice_region_variant | 28/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 18, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been rarely reported (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) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative changes, p.(Asp1155Val) and p.(Asp1155Gly), have been submitted to ClinVar once each as likely pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and has been observed in individuals with Marfan syndrome, ectopia lentis, aortic disease and/or striae atrophica with inguinal or umbilical herniae (ClinVar, PMID: 14695540). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2020 | 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 21, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Stiff skin syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 22, 2022 | - - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2022 | 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. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at