Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035155 | SCV000058796 | uncertain significance | not specified | 2008-05-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000588311 | SCV000233773 | uncertain significance | not provided | 2023-05-09 | criteria provided, single submitter | clinical testing | Reported in association with Marfan syndrome; however, at least one patient harbored a second FBN1 variant (p. C534Y) which was suspected to be the cause of disease (Comeglio et al., 2007; Wooderchak-Donahue et al., 2015; Vatti et al., 2017; Lerner-Ellis et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32123317, 28941062, 25637381, 25812041, 27647783, 24941995, 21895641, 25944730, 31211626, 24793577, 26633542, 25839328, 35130036, 17657824) |
| Invitae | RCV000528908 | SCV000627875 | likely benign | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-12-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588311 | SCV000695498 | likely benign | not provided | 2017-03-27 | criteria provided, single submitter | clinical testing | Variant summary: The FBN1 c.2927G>A (p.Arg976His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within a TB domain (InterPro) and 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing, but ESE finder predicts that this variant may affect several ESE sites at the locus. However, a functional study determined that the variant had no effect on splicing via RNA analysis in patient blood samples (Robinson_ClinGen_2012). This variant was found in the large control database ExAC at a frequency of 0.00014 (17/121462 control chromosomes), which is slightly above estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this variant is likely a benign polymorphism. The variant was also detected in a patient cohort co-occurring with a likely pathogenic variant (Lerner-Ellis_MGM_2014; p.Cys534Tyr), further supporting the benign nature of the variant of interest. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance; however, 2 of the entries were reported prior to the release of the ExAC database, and 1 entry (from 2016) cites only the ESP database as a source for control population data (GeneDx; see description provided below in the ClinVar additional comments). Taken together, this variant is classified as likely benign. |
| Color Diagnostics, |
RCV000777744 | SCV000913705 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-03-20 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with histidine at codon 976 of the FBN1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Marfan syndrome (PMID: 17657824, 21895641, 25944730, 28941062). It has also been reported in an individual affected with clinical features of Marfan syndrome who also carried a different pathogenic missense variant in the same gene (PMID: 24793577). This variant has been identified in 29/282840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. |
| ARUP Laboratories, |
RCV000588311 | SCV001474399 | uncertain significance | not provided | 2023-09-21 | criteria provided, single submitter | clinical testing | The FBN1 c.2927G>A; p.Arg976His variant (rs140954477) is reported in the literature in individuals with symptoms of Marfan syndrome (Comeglio 2007, Robinson 2012), but is also reported in Marfan syndrome patient who also carried a likely pathogenic FBN1 variant (Lerner-Ellis 2014). This variant is reported in ClinVar (Variation ID: 42321), and is found in the general population with an overall allele frequency of 0.01% (29/282840 alleles) in the Genome Aggregation Database. The arginine at codon 976 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.862). While the population frequency (Yang 2014) and presence in a patient with a different disease-causing variant (Lerner-Ellis 2014) suggest that this variant does not cause disease, given the minimal clinical and functional data, the significance of the p.Arg976His variant is uncertain at this time. References: Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Lerner-Ellis JP et al. The spectrum of FBN1, TGFßR1, TGFßR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014 Jun;112(2):171-6. Robinson DO et al. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities. Clin Genet. 2012 Sep;82(3):223-31. Yang RQ et al. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome. BMC Genet. 2014 Jun 18;15:74. |
| CHEO Genetics Diagnostic Laboratory, |
RCV000777744 | SCV002041966 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2021-11-10 | criteria provided, single submitter | clinical testing | |
| Genome Diagnostics Laboratory, |
RCV002277119 | SCV002566519 | uncertain significance | Connective tissue disorder | 2019-12-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000777744 | SCV002748536 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2021-02-08 | criteria provided, single submitter | clinical testing | The p.R976H variant (also known as c.2927G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2927. The arginine at codon 976 is replaced by histidine, an amino acid with highly similar properties, and is located in the TGFBP#03 domain. This variant was reported in a patient described to have classic Marfan syndrome (MS) (Comeglio P et al. Hum Mutat. 2007;28(9):928) and in cohorts of individuals with symptoms of Marfan syndrome (Robinson DO et al. Clin Genet. 2012;82(3):223-31; Wooderchak-Donahue W et al. Am. J. Med. Genet. A. 2015;167A:1747-57; Vatti L et al. Am. J. Med. Genet. A. 2017:epub ahead of print); however, clinical details were limited in all studies. This variant has also been seen in exome cohorts not selected for presence of MFS or cardiovascular findings; however, clinical history was limited or not provided (Yang RQ et al. BMC Genet. 2014;15:74; Amendola LM et al. Genome Res. 2015;25(3):305-15; Retterer K et al. Genet Med. 2016 07;18(7):696-704; Damrauer SM et al. Circ Genom Precis Med. 2019 06;12(6):e002454). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. |
| CSER _CC_NCGL, |
RCV000148497 | SCV000190206 | uncertain significance | Marfan syndrome | 2014-06-01 | no assertion criteria provided | research |