ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2927G>A (p.Arg976His) (rs140954477)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035155 SCV000058796 uncertain significance not specified 2008-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000588311 SCV000233773 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing p.Arg976His (CGC>CAC): c.2927 G>A in exon 25 in the FBN1 gene (NM_000138.4). The R976H variant in the FBN1 gene has been reported previously in a 22 year-old patient with classic Marfan syndrome, however detailed clinical information was not published on this individual (Comeglio et al., 2007). This variant is a conservative substitution of one positively-charged and polar amino acid for another at a residue that is conserved across species. In silico analysis was inconsistent with regards to the effect this variant may have on the protein structure/function. The R976H variant was not observed at any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R976H variant is a good candidate for a disease-causing pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. The variant is found in FBN1, panel(s).
Invitae RCV000528908 SCV000627875 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-04-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 976 of the FBN1 protein (p.Arg976His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140954477, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with Marfan syndrome (PMID: 1765782, 21895641, 25944730, 28941062). ClinVar contains an entry for this variant (Variation ID: 42321). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
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 Health, Inc RCV000777744 SCV000913705 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-12-14 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 deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 3 individuals affected with Marfan syndrome (PMID: 17657824, 21895641, 28941062). 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 RCV001287687 SCV001474399 uncertain significance none provided 2019-07-31 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 (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. 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.
CSER _CC_NCGL, University of Washington RCV000148497 SCV000190206 uncertain significance Marfan syndrome 2014-06-01 no assertion criteria provided research

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