ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7661G>A (p.Arg2554Gln) (rs199522781)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766961 SCV000616717 uncertain significance not provided 2018-07-03 criteria provided, single submitter clinical testing The R2554Q variant of uncertain significance in the FBN1 gene has been reported previously in one individual with features of Marfan syndrome; however, she did not meet Ghent criteria, and no segregation data was provided (Sheikhzadeh et al., 2012). In addition, R2554Q has been identified in two other individuals referred for Marfan syndrome, TAAD, and related disorders testing at GeneDx, but segregation data is absent due to insufficient participation by informative family members. The R2554Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this variant occurs at a position where only amino acids with similar properties to arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Although located within a calcium-binding EGF-like domain of the FBN1 gene, the R2554Q variant does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003). Finally, the R2554Q variant was observed in 7/6,278 (0.11%) alleles from individuals of European (Finnish) ancestry in the Exome Aggregation Consortium (Lek et al., 2016).
Illumina Clinical Services Laboratory,Illumina RCV000382117 SCV000392124 likely benign Acromicric dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290065 SCV000392125 likely benign Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000347326 SCV000392126 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000396029 SCV000392127 likely benign Weill-Marchesani syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313030 SCV000392128 likely benign Ectopia lentis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000351514 SCV000392129 likely benign MASS syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000400646 SCV000392130 likely benign Stiff skin syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297567 SCV000392131 likely benign Geleophysic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000632066 SCV000753169 likely benign Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-12-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454621 SCV000539149 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2/3 papers in HGMD classify as VUS; ExAC: 0.1% (7/6278) Finnish chromosomes

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