Submissions for variant NM_000138.5(FBN1):c.2927G>A (p.Arg976His)

gnomAD frequency: 0.00005  dbSNP: rs140954477

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035155	SCV000058796	uncertain significance	not specified	2008-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000588311	SCV000233773	uncertain significance	not provided	2024-04-09	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 (PMID: 17657824, 25944730, 28941062, 24793577); Although located in a TGF-binding protein domain (aka TB domain or 8-Cysteine domain), it does not affect a cysteine residue within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes (HGMD); 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: 28941062, 25637381, 25812041, 27647783, 24941995, 21895641, 25944730, 31211626, 24793577, 26633542, 25839328, 35130036, 34663891, 17657824, 32123317)
Labcorp Genetics (formerly Invitae), Labcorp	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, LabCorp	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, LLC DBA Color Health	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, Molecular Genetics and Genomics, 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, Children's Hospital of Eastern Ontario	RCV000777744	SCV002041966	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	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	2024-01-03	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). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 conflicting at this time, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000148497	SCV004808033	likely benign	Marfan syndrome	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000148497	SCV004814853	uncertain significance	Marfan syndrome	2024-01-11	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.
CSER _CC_NCGL, University of Washington	RCV000148497	SCV000190206	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004737171	SCV005345413	uncertain significance	FBN1-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The FBN1 c.2927G>A variant is predicted to result in the amino acid substitution p.Arg976His. This variant has been reported in multiple individuals with Marfan syndrome; however, clinical information was limited and family studies were not reported to help assess the variant's pathogenicity (Comeglio et al. 2007. PubMed ID: 17657824; Robinson et al. 2011. PubMed ID: 21895641; Wooderchak-Donahue et al. 2015. PubMed ID: 25944730; Groth et al. 2015. PubMed ID: 25812041). This variant has also been reported in individuals without Marfan syndrome (Damrauer et al. 2019. PubMed ID: 31211626) and, in one study, reported in an individual with features of Marfan syndrome who harbored an additional variant in FBN1 that was more likely to explain the phenotype (Table S6, Lerner-Ellis et al. 2014. PubMed ID: 24793577). This variant is reported in 0.015% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations in the ClinVar database, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/42321/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.