ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6388G>A (p.Glu2130Lys) (rs794728334)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181698 SCV000234001 pathogenic not provided 2014-09-23 criteria provided, single submitter clinical testing p.Glu2130Lys (GAA>AAA): c.6388 G>A in exon 53 of the FBN1 gene (NM_000138.4)The E2130K mutation in the FBN1 gene has been reported previously in individuals meeting Ghent criteria forMarfan syndrome (Tjedhorn et al., 2006; Stheneur et al., 2009; Attanasio et al., 2008) and in one individualwith aortic dilation, mitral valve prolapse and skeletal involvement who did not meet criteria (Chung et al.,2009). E2130K was absent from >200 control alleles (Tjedhorn et al., 2006; Stheneur et al., 2009; Attanasio etal., 2008). Additionally, the E2130K mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E2130K results in a non-conservative amino acid substitution at aposition that is class conserved across species. Additionally, mutations in nearby residues (G2140E, G2140R,V2136D, D2127E, D2127V, D2127Y) have been reported in association with FBN1-related disorders, further supporting the functional importance of this region of the protein. In summary, E2130K in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000181698 SCV000603625 pathogenic not provided 2017-08-20 criteria provided, single submitter clinical testing The FBN1 c.6388G>A, p.Glu2130Lys variant has been reported in multiple individuals diagnosed with Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007, Attanasio 2008, Stheneur 2009). It is listed in the ClinVar database (Variation ID: 200191), in the dbSNP variant database (rs794728334), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The glutamine at residue 2130 is highly conserved, lies in the cbEGF domain, and any variation in the conserved residues of the consensus sequence is considered pathogenic (Loeys 2010). Additionally, computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Attanasio M et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet. 2008 74(1):39-46. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007 143A(17):1968-77. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 17(9):1121-8 Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64.
Ambry Genetics RCV000618917 SCV000738927 likely pathogenic Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Center for Human Genetics, Inc RCV000659564 SCV000781398 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768213 SCV000898689 likely pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-09-07 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 53 p.Glu2130Lys (c.6388G>A): This variant has been reported in the literature in at least 5 individuals meeting Ghent criteria for Marfan syndrome (Tjeldhorn 2006 PMID:17253931, Rand-Hendriksen 2007 PMID:17663468, Attanasio 2008 PMID:18435798, Stheneur 2009 PMID:19293843, Al-Haggar 2017 PMID:28098115, Zhang 2018 PMID:29845260) and in one female with suspected Marfan syndrome who did not meet Ghent criteria (Chung 2009 PMID:19533785). This variant was also reported to segregate with disease in at least 3 affected family members (Al-Haggar 2017 PMID:28098115). This variant is not present in large control databases. It is present in ClinVar, with several labs classifying this variant as likely pathogenic or pathogenic (Variation ID:200191). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Invitae RCV000824568 SCV000965470 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2130 of the FBN1 protein (p.Glu2130Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Marfan syndrome in a family (PMID: 28098115). It has also been reported in other unrelated affected individuals (PMID: 17253931, 19533785, 19293843, Invitae). ClinVar contains an entry for this variant (Variation ID: 200191). 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"). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000659564 SCV000787225 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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