ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.8027C>T (p.Pro2676Leu) (rs146469379)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765218 SCV000896454 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 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000483455 SCV000564996 uncertain significance not provided 2017-07-08 criteria provided, single submitter clinical testing The P2676L variant of uncertain significance in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. The P2676L variant is observed in 6/10394 (0.06%) alleles from individuals of African background in the Exome Aggregation Consortium dataset (Lek et al., 2016). The P2676L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, this substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although P2676L is located within a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000697974 SCV000826610 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2676 of the FBN1 protein (p.Pro2676Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs146469379, ExAC 0.06%). This variant has not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 418202). 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 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.

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