ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2953G>A (p.Gly985Arg) (rs794728199)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181473 SCV000233775 likely pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The G985R variant in the FBN1 gene has been reported in multiple unrelated individuals diagnosed with classic Marfan syndrome or Marfan-like features (Loeys et al., 2001; Rommel et al., 2005; Faivre et al., 2009; Turner et al., 2009; Howarth et al, 2007; Ware et al., 2016). In addition, the G985R variant is not observed in large population cohorts (Lek et al., 2016). The G985R variant is classified as likely pathogenic and pathogenic in ClinVar by outside laboratories (SCV000695500.1; SCV000319440.3; SCV000627877.1; Landrum et al., 2016). Although this variant has been published in association with Marfan syndrome or Marfan-like features, it is lacking functional analysis and segregation studies, which would clarify its pathogenicity. Furthermore, Yang et al. (2016) reclassified the variant from likely pathogenic to benign based on non-segregation in one family, though no clinical details are provided.The G985R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, a variant in the same residue (G985E) has been reported in HGMD and at GeneDx in association with Marfan syndrome (Stenson et al., 2014), further supporting the functional importance of this residue.
Ambry Genetics RCV000249898 SCV000319440 likely pathogenic Cardiovascular phenotype 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000549578 SCV000627877 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 985 of the FBN1 protein (p.Gly985Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple unrelated individuals with Marfan syndrome or FBN1-related conditions (PMID: 11700157, 16220557, 17627385, 19863550, 24199744), including several who fulfilled the Ghent criteria for a diagnosis of Marfan syndrome. ClinVar contains an entry for this variant (Variation ID: 200008). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586105 SCV000695500 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-06-21 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.2953G>A (p.Gly985Arg) missense variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools. This variant is located in TB domain and glycines in the FBN1 gene are implicated in correct domain-domain packing (Faive_2009). This variant is absent in 121470 control chromosomes (including ExAC). This variant has been reported in several MFS (classic as well as incomplete MFS) patients. In one family, this variant was found in three affected members with MFS or MFS-like syndrome but not in five unaffected members, indicating cosegregation with disease (Howarth_2007). In two other families, probands affected with classic MFS and two first-degree relatives in each family carried the variant; however affected status of the family members was not clearly indicated (Ware_2016). In contrast to the pathogenic outcome from these three families, a study reclassified this variant to benign from family segregation analysis (Yang_2016). However, genotypic and phenotypic details of family members were not provided, limiting independent evaluation of the evidences. Two clinical diagnostic laboratories (via ClinVar) have classified this variant as likely pathogenic (one has noted the finding of Yang_2016). Another missense change at the same residue G985E has also been reported in a patient with MFS, suggesting that Gly985 codon could be mutational hot-spot. Based on the currently available data, this variant is classified as likely pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663591 SCV000786905 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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