ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4998C>G (p.Thr1666=) (rs141925790)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621602 SCV000738754 likely benign Cardiovascular phenotype 2016-01-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761912 SCV000892132 likely benign not provided 2018-09-30 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768215 SCV000898691 uncertain significance Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2017-09-19 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 41 p.Thr1666Thr (c.4998C>G): This variant has been reported in the literature in 1 individual with Marfan syndrome (Franken 2016 PMID:26787436). This variant is present in 12/111516 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs141925790). This variant is present in ClinVar (Variation ID:381319). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx RCV000417854 SCV000520519 likely benign not specified 2017-01-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000417854 SCV000919331 benign not specified 2018-03-07 criteria provided, single submitter clinical testing Variant summary: FBN1 c.4998C>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9e-05 in 276932 control chromosomes from gnomAD. The observed variant frequency within Non-Finnish European control individuals (23/126526 chromosomes) is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.4998C>G variant has been reported in the literature in two individuals potentially affected with Marfan Syndrome. However, these reports do not provide unequivocal conclusions about an association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000473666 SCV000557031 likely benign Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-03-20 criteria provided, single submitter clinical testing

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